60 results on '"Herranz-Pérez V"'
Search Results
2. Mouse paralaminar amygdala excitatory neurons migrate and mature during adolescence
- Author
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Alderman, P.J., primary, Saxon, D., additional, Torrijos-Saiz, L.I., additional, Sharief, M., additional, Biagiotti, S.W., additional, Page, C.E., additional, Melamed, A., additional, Kuo, C.T., additional, Garcia-Verdugo, J.M., additional, Herranz-Pérez, V., additional, Corbin, J.G., additional, and Sorrells, S.F., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Localization of GFP-Tagged Proteins at the Electron Microscope
- Author
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Gil-Perotin, Sara, primary, Cebrián-Silla, A., additional, Herranz-Pérez, V., additional, García-Belda, P., additional, Gil-García, S., additional, Fil, M., additional, Lee, J. S., additional, Nachury, M. V., additional, and García-Verdugo, José Manuel, additional
- Published
- 2016
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4. Heterogeneous Pattern of Differentiation With BCAS1/NABC1 Expression in a Case of Oligodendroglioma
- Author
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Ulloa-Navas MJ, Rubio L, Teruel-Sanchis A, Peña-Peña J, García-Verdugo JM, Herranz-Pérez V, and Ferrer-Lozano J
- Published
- 2021
5. Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates
- Author
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Duro-Castano, A., primary, Borrás, C., additional, Herranz-Pérez, V., additional, Blanco-Gandía, M. C., additional, Conejos-Sánchez, I., additional, Armiñán, A., additional, Mas-Bargues, C., additional, Inglés, M., additional, Miñarro, J., additional, Rodríguez-Arias, M., additional, García-Verdugo, J. M., additional, Viña, J., additional, and Vicent, M. J., additional
- Published
- 2021
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6. New neurons use Slit-Robo signaling to migrate through the glial meshwork and approach a lesion for functional regeneration
- Author
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Kaneko, N., primary, Herranz-Pérez, V., additional, Otsuka, T., additional, Sano, H., additional, Ohno, N., additional, Omata, T., additional, Nguyen, H. B., additional, Thai, T. Q., additional, Nambu, A., additional, Kawaguchi, Y., additional, García-Verdugo, J. M., additional, and Sawamoto, K., additional
- Published
- 2018
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7. The aged brain: genesis and fate of residual progenitor cells in the subventricular zone
- Author
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Capilla-Gonzalez V, Herranz-Pérez V, and García-Verdugo JM
- Subjects
neurogenesis ,nervous system ,rostral migratory stream ,oligodendrogenesis ,cell migration ,aging ,subventricular zone ,neural stem cells - Abstract
Neural stem cells (NSCs) persist in the adult mammalian brain through life. The subventricular zone (SVZ) is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the SW suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence.
- Published
- 2015
8. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation
- Author
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Laurent Pasquier, Bernard Aral, Jaclyn S Lee, Judith St-Onge, Michel Vekemans, Frédéric Huet, Brunella Franco, Fan Ye, Philippe Loget, Ange-Line Bruel, Arnold Munnich, Nadège Gigot, Carla A.M. Lopes, Sophie Saunier, José Manuel García-Verdugo, Julien Thevenon, Vicente Herranz-Pérez, Susana González-Granero, Laurence Jego, Maxence V. Nachury, André Mégarbané, Jean-Baptiste Rivière, Laurence Faivre, Caroline Alby, Toshinobu Shida, Christel Thauvin-Robinet, Andrew M. Fry, Estelle Lopez, Tania Attié-Bitach, Thauvin Robinet, C, Lee, J, Lopez, E, Herranz Pérez, V, Shida, T, Franco, Brunella, Jego, L, Ye, F, Pasquier, L, Loget, P, Gigot, N, Aral, B, Lopes, Ca, St Onge, J, Bruel, Al, Thevenon, J, González Granero, S, Alby, C, Munnich, A, Vekemans, M, Huet, F, Fry, Am, Saunier, S, Rivière, Jb, Attié Bitach, T, Garcia Verdugo, Jm, Faivre, L, Mégarbané, A, and Nachury, M. V.
- Subjects
Male ,Microcephaly ,Centriole ,Microtubule-associated protein ,sports ,Biology ,Ciliopathies ,Centriole elongation ,Article ,Cell Line ,Procentriole ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Centrioles ,Cilium ,Proteins ,Orofaciodigital Syndromes ,medicine.disease ,sports.league ,HEK293 Cells ,Centrosome ,Child, Preschool ,Microtubule-Associated Proteins - Abstract
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia(1,2). How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth(3-5), whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation(6,7). Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.
- Published
- 2014
9. Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.
- Author
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Zufiría M, Pikatza-Menoio O, Garciandia-Arcelus M, Bengoetxea X, Jiménez A, Elicegui A, Levchuk M, Arnold-García O, Ondaro J, Iruzubieta P, Rodríguez-Gómez L, Fernández-Pelayo U, Muñoz-Oreja M, Aiastui A, García-Verdugo JM, Herranz-Pérez V, Zulaica M, Poza JJ, Ruiz-Onandi R, Fernández-Torrón R, Espinal JB, Bonilla M, Lersundi A, Fernández-Eulate G, Riancho J, Vallejo-Illarramendi A, Holt IJ, Sáenz A, Malfatti E, Duguez S, Blázquez L, López de Munain A, Gerenu G, Gil-Bea F, and Alonso-Martín S
- Subjects
- Humans, Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Male, RNA-Binding Protein FUS genetics, RNA-Binding Protein FUS metabolism, Female, Drosophila, Muscle Development physiology, Middle Aged, Aged, Motor Neurons metabolism, Motor Neurons pathology, Myoblasts metabolism, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Forkhead Box Protein O1 metabolism, Forkhead Box Protein O1 genetics
- Abstract
Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue., (© 2024. The Author(s).)
- Published
- 2024
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10. Neuraminidase inhibition promotes the collective migration of neurons and recovery of brain function.
- Author
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Matsumoto M, Matsushita K, Hane M, Wen C, Kurematsu C, Ota H, Bang Nguyen H, Quynh Thai T, Herranz-Pérez V, Sawada M, Fujimoto K, García-Verdugo JM, Kimura KD, Seki T, Sato C, Ohno N, and Sawamoto K
- Subjects
- Animals, Mice, Zanamivir pharmacology, Enzyme Inhibitors pharmacology, Sialic Acids metabolism, Brain Injuries drug therapy, Brain Injuries metabolism, Recovery of Function drug effects, Mice, Inbred C57BL, Cell Adhesion drug effects, Humans, Male, Neuraminidase metabolism, Neuraminidase antagonists & inhibitors, Cell Movement drug effects, Neurons drug effects, Neurons metabolism, Brain
- Abstract
In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell-cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning., (© 2024. The Author(s).)
- Published
- 2024
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11. Identification of the growth cone as a probe and driver of neuronal migration in the injured brain.
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Nakajima C, Sawada M, Umeda E, Takagi Y, Nakashima N, Kuboyama K, Kaneko N, Yamamoto S, Nakamura H, Shimada N, Nakamura K, Matsuno K, Uesugi S, Vepřek NA, Küllmer F, Nasufović V, Uchiyama H, Nakada M, Otsuka Y, Ito Y, Herranz-Pérez V, García-Verdugo JM, Ohno N, Arndt HD, Trauner D, Tabata Y, Igarashi M, and Sawamoto K
- Subjects
- Mice, Animals, Neurogenesis, Axons metabolism, Chondroitin Sulfates metabolism, Brain metabolism, Cells, Cultured, Growth Cones metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 2 genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 2 metabolism
- Abstract
Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration., (© 2024. The Author(s).)
- Published
- 2024
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12. Delayed maturation and migration of excitatory neurons in the juvenile mouse paralaminar amygdala.
- Author
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Alderman PJ, Saxon D, Torrijos-Saiz LI, Sharief M, Page CE, Baroudi JK, Biagiotti SW, Butyrkin VA, Melamed A, Kuo CT, Vicini S, García-Verdugo JM, Herranz-Pérez V, Corbin JG, and Sorrells SF
- Subjects
- Adolescent, Humans, Adult, Animals, Mice, Neurons, Amygdala, Affect, Neural Stem Cells, Basolateral Nuclear Complex
- Abstract
The human amygdala paralaminar nucleus (PL) contains many immature excitatory neurons that undergo prolonged maturation from birth to adulthood. We describe a previously unidentified homologous PL region in mice that contains immature excitatory neurons and has previously been considered part of the amygdala intercalated cell clusters or ventral endopiriform cortex. Mouse PL neurons are born embryonically, not from postnatal neurogenesis, despite a subset retaining immature molecular and morphological features in adults. During juvenile-adolescent ages (P21-P35), the majority of PL neurons undergo molecular, structural, and physiological maturation, and a subset of excitatory PL neurons migrate into the adjacent endopiriform cortex. Alongside these changes, PL neurons develop responses to aversive and appetitive olfactory stimuli. The presence of this homologous region in both humans and mice points to the significance of this conserved mechanism of neuronal maturation and migration during adolescence, a key time period for amygdala circuit maturation and related behavioral changes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Protracted neuronal recruitment in the temporal lobes of young children.
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Nascimento MA, Biagiotti S, Herranz-Pérez V, Santiago S, Bueno R, Ye CJ, Abel TJ, Zhang Z, Rubio-Moll JS, Kriegstein AR, Yang Z, Garcia-Verdugo JM, Huang EJ, Alvarez-Buylla A, and Sorrells SF
- Subjects
- Animals, Child, Preschool, Humans, Infant, Entorhinal Cortex cytology, Entorhinal Cortex physiology, Ganglionic Eminence cytology, Interneurons cytology, Interneurons physiology, Macaca mulatta, Single-Cell Gene Expression Analysis, Cell Movement, Neurons cytology, Neurons physiology, Temporal Lobe cytology, Temporal Lobe growth & development
- Abstract
The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs
1-4 . The human EC continues to develop during childhood5 , but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+ RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+ RELN+ cells6,7 . Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood., (© 2023. The Author(s).)- Published
- 2024
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14. Regulation of young-adult neurogenesis and neuronal differentiation by neural cell adhesion molecule 2 (NCAM2).
- Author
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Ortega-Gascó A, Parcerisas A, Hino K, Herranz-Pérez V, Ulloa F, Elias-Tersa A, Bosch M, García-Verdugo JM, Simó S, Pujadas L, and Soriano E
- Subjects
- Mice, Animals, Cell Differentiation physiology, Neural Cell Adhesion Molecules metabolism, Hippocampus metabolism, Mammals metabolism, Neurons physiology, Neurogenesis physiology
- Abstract
Adult neurogenesis persists in mammals in the neurogenic zones, where newborn neurons are incorporated into preexisting circuits to preserve and improve learning and memory tasks. Relevant structural elements of the neurogenic niches include the family of cell adhesion molecules (CAMs), which participate in signal transduction and regulate the survival, division, and differentiation of radial glial progenitors (RGPs). Here we analyzed the functions of neural cell adhesion molecule 2 (NCAM2) in the regulation of RGPs in adult neurogenesis and during corticogenesis. We characterized the presence of NCAM2 across the main cell types of the neurogenic process in the dentate gyrus, revealing different levels of NCAM2 amid the progression of RGPs and the formation of neurons. We showed that Ncam2 overexpression in adult mice arrested progenitors in an RGP-like state, affecting the normal course of young-adult neurogenesis. Furthermore, changes in Ncam2 levels during corticogenesis led to transient migratory deficits but did not affect the survival and proliferation of RGPs, suggesting a differential role of NCAM2 in adult and embryonic stages. Our data reinforce the relevance of CAMs in the neurogenic process by revealing a significant role of Ncam2 levels in the regulation of RGPs during young-adult neurogenesis in the hippocampus., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
- Published
- 2023
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15. Normal pressure hydrocephalus decreases the proliferation of oligodendrocyte progenitor cells and the expression of CNPase and MOG proteins in the corpus callosum before behavioral deficits occur.
- Author
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Campos-Ordoñez T, González-Granero S, Eudave-Patiño M, Buriticá J, Herranz-Pérez V, García-Verdugo JM, and Gonzalez-Perez O
- Subjects
- Mice, Animals, Corpus Callosum, 2',3'-Cyclic-Nucleotide Phosphodiesterases genetics, Myelin Sheath, Oligodendroglia, Myelin Proteins, Cell Proliferation, Hydrocephalus, Normal Pressure, Oligodendrocyte Precursor Cells
- Abstract
Normal pressure hydrocephalus (NPH) compromises the morphology of the corpus callosum (CC). This study aims to determine whether 60- or 120-day NPH disrupts the cytoarchitecture and functioning of white matter (WM) and oligodendrocyte precursor cells (OPCs) and establish whether these changes are reversible after hydrocephalus treatment. NPH was induced in CD1 adult mice by inserting an obstructive lamina in the atrium of the aqueduct of Sylvius. Five groups were assembled: sham-operated controls (60 and 120 days), NPH groups (60 and 120 days), and the hydrocephalus-treated group (obstruction removal after 60-d hydrocephalus). We analyzed the cellular integrity of the CC by immunohistochemistry, TUNEL analysis, Western blot assays, and transmission electron microscopy (TEM). We found a reduction in the width of the CC at 60 and 120 days of NPH. TEM analysis demonstrated myelin abnormalities, degenerative changes in the WM, and an increase in the number of hyperdense (dark) axons that were associated with significant astrogliosis, and microglial reactivity. Hydrocephalus also caused a decrease in the expression of myelin-related proteins (MOG and CNPase) and reduced proliferation and population of OPCs, resulting in fewer mature oligodendrocytes. Hydrocephalus resolution only recovers the OPC proliferation and MOG protein density, but the rest of the WM abnormalities persisted. Interestingly, all these cellular and molecular anomalies occur in the absence of behavioral changes. The results suggest that NPH severely disrupts the myelin integrity and affects the OPC turnover in the CC. Remarkably, most of these deleterious events persist after hydrocephalus treatment, which suggests that a late treatment conveys irreversible changes in the WM of CC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Oscar Gonzalez-Perez reports financial support, administrative support, article publishing charges, statistical analysis, travel, and writing assistance were provided by Consejo Nacional de Ciencia y Tecnología, MX., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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16. Amphiphilic peptide-tagged N-cadherin forms radial glial-like fibers that enhance neuronal migration in injured brain and promote sensorimotor recovery.
- Author
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Ohno Y, Nakajima C, Ajioka I, Muraoka T, Yaguchi A, Fujioka T, Akimoto S, Matsuo M, Lotfy A, Nakamura S, Herranz-Pérez V, García-Verdugo JM, Matsukawa N, Kaneko N, and Sawamoto K
- Subjects
- Animals, Brain, Neurons, Peptides, Mammals, Cadherins, Neural Stem Cells
- Abstract
The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)
3 -(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
- Full Text
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17. Adult neurogenesis in the telencephalon of the lizard Podarcis liolepis .
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González-Granero S, Font E, Desfilis E, Herranz-Pérez V, and García-Verdugo JM
- Abstract
In adult lizards, new neurons are generated from neural stem cells in the ventricular zone of the lateral ventricles. These new neurons migrate and integrate into the main telencephalic subdivisions. In this work we have studied adult neurogenesis in the lizard Podarcis liolepis (formerly Podarcis hispanica ) by administering [
3 H]-thymidine and bromodeoxyuridine as proliferation markers and euthanizing the animals at different survival times to determine the identity of progenitor cells and to study their lineage derivatives. After short survival times, only type B cells are labeled, suggesting that they are neural stem cells. Three days after administration, some type A cells are labeled, corresponding to recently formed neuroblasts. Type A cells migrate to their final destinations, where they differentiate into mature neurons and integrate into functional circuits. Our results after long survival periods suggest that, in addition to actively dividing type B cells, there is also a type B subpopulation with low proliferative activity. We also found that new neurons incorporated into the olfactory bulb are generated both in situ , in the walls of the anterior extension of the lateral ventricle of the olfactory bulbs, but also at more caudal levels, most likely in anterior levels of the sulcus ventralis/terminalis. These cells follow a tangential migration toward the olfactory bulbs where they integrate. We hypothesized that at least part of the newly generated neurons would undergo a specialization process over time. In support of this prediction, we found two neuronal populations in the cellular layer of the medial cortex, which we named type I and II neurons. At intermediate survival times (1 month) only type II neurons were labeled with [3 H]-thymidine, while at longer survival times (3, 6, or 12 months) both type I and type II neurons were labeled. This study sheds light on the ultrastructural characteristics of the ventricular zone of P. liolepis as a neurogenic niche, and adds to our knowledge of the processes whereby newly generated neurons in the adult brain migrate and integrate into their final destinations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 González-Granero, Font, Desfilis, Herranz-Pérez and García-Verdugo.)- Published
- 2023
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18. Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis.
- Author
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Hall EA, Kumar D, Prosser SL, Yeyati PL, Herranz-Pérez V, García-Verdugo JM, Rose L, McKie L, Dodd DO, Tennant PA, Megaw R, Murphy LC, Ferreira MF, Grimes G, Williams L, Quidwai T, Pelletier L, Reiter JF, and Mill P
- Subjects
- Animals, Female, Humans, Mice, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Centrosome metabolism, Cytoskeletal Proteins metabolism, Centrioles metabolism, Cilia metabolism
- Abstract
Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1
-/- mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1-/- multiciliated ependymal cells and human PCM1-/- retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1-/- RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1-/- ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types., Competing Interests: EH, DK, SP, PY, VH, JG, LR, LM, DD, PT, RM, LM, MF, GG, LW, TQ, LP, PM No competing interests declared, JR Reviewing editor, eLife, (© 2023, Hall, Kumar et al.)- Published
- 2023
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19. Plasticity of cell proliferation in the retina of Austrolebias charrua fish under light and darkness conditions.
- Author
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Berrosteguieta I, Rosillo JC, Herrera ML, Olivera-Bravo S, Casanova G, Herranz-Pérez V, García-Verdugo JM, and Fernández AS
- Abstract
Austrolebias annual fishes exhibit cell proliferation and neurogenesis throughout life. They withstand extreme environmental changes as their habitat dries out, pressuring nervous system to adapt. Their visual system is challenged to adjust as the water becomes turbid. Therefore, this study focused on how change in photic environment can lead to an increased cell proliferation in the retina. We administered 5-chloro-2'- deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU) at different temporal windows to detect cell proliferation in natural light and permanent darkness. Stem/progenitor cells were recognized as IdU+/CldU + nuclei co-labeled with Sox2, Pax6 or BLBP found in the ciliary marginal zone (CMZ). The expression pattern of BLBP + glial cells and ultrastructural analysis indicates that CMZ has different cell progenitors. In darkness, the number of dividing cells significantly increased, compared to light conditions. Surprisingly, CMZ IdU+/CldU + cell number was similar under light and darkness, suggesting a stable pool of stem/progenitor cells possibly responsible for retinal growth. Therefore, darkness stimulated cell progenitors outside the CMZ, where Müller glia play a crucial role to generate rod precursors and other cell types that might integrate rod-dependent circuits to allow darkness adaptation. Thus, the Austrolebias fish retina shows great plasticity, with cell proliferation rates significantly higher than that of brain visual areas., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)
- Published
- 2022
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20. Editorial: Mesenchymal Stromal Cell Therapy for Regenerative Medicine.
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Capilla-González V, Herranz-Pérez V, Sarabia-Estrada R, Kadri N, and Moll G
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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21. Editorial: New Insights Into Adult Neurogenesis and Neurodegeneration: Challenges for Brain Repair.
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Morales-García JA, Kaneko N, and Herranz-Pérez V
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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22. Ependymoma associated protein Zfta is expressed in immature ependymal cells but is not essential for ependymal development in mice.
- Author
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Herranz-Pérez V, Nakatani J, Ishii M, Katada T, García-Verdugo JM, and Ohata S
- Subjects
- Animals, Mice, Cilia metabolism, Gene Expression Regulation, Developmental, Lateral Ventricles metabolism, Transcription Factor RelA metabolism, Transcription Factor RelA genetics, Ependyma metabolism, Ependymoma metabolism, Ependymoma genetics, Ependymoma pathology, Translocation, Genetic
- Abstract
The fusion protein of uncharacterised zinc finger translocation associated (ZFTA) and effector transcription factor of tumorigenic NF-κB signalling, RELA (ZFTA-RELA), is expressed in more than two-thirds of supratentorial ependymoma (ST-EPN-RELA), but ZFTA's expression profile and functional analysis in multiciliated ependymal (E1) cells have not been examined. Here, we showed the mRNA expression of mouse Zfta peaks on embryonic day (E) 17.5 in the wholemount of the lateral walls of the lateral ventricle. Zfta was expressed in the nuclei of FoxJ1-positive immature E1 (pre-E1) cells in E18.5 mouse embryonic brain. Interestingly, the transcription factors promoting ciliogenesis (ciliary TFs) (e.g., multicilin) and ZFTA-RELA upregulated luciferase activity using a 5' upstream sequence of ZFTA in cultured cells. Zfta
tm1/tm1 knock-in mice did not show developmental defects or abnormal fertility. In the Zftatm1/tm1 E1 cells, morphology, gene expression, ciliary beating frequency and ependymal flow were unaffected. These results suggest that Zfta is expressed in pre-E1 cells, possibly under the control of ciliary TFs, but is not essential for ependymal development or flow. This study sheds light on the mechanism of the ZFTA-RELA expression in the pathogenesis of ST-EPN-RELA: Ciliary TFs initiate ZFTA-RELA expression in pre-E1 cells, and ZFTA-RELA enhances its own expression using positive feedback., (© 2022. The Author(s).)- Published
- 2022
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23. Endoderm development requires centrioles to restrain p53-mediated apoptosis in the absence of ERK activity.
- Author
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Xie C, Abrams SR, Herranz-Pérez V, García-Verdugo JM, and Reiter JF
- Subjects
- Animals, Cell Survival, Endoderm metabolism, Epithelial Cells metabolism, Intestines growth & development, Lung embryology, Mice, Inbred C57BL, Microtubule-Associated Proteins metabolism, Morphogenesis, SOXB1 Transcription Factors metabolism, Stem Cells metabolism, Mice, Apoptosis, Centrioles metabolism, Endoderm embryology, Extracellular Signal-Regulated MAP Kinases metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Centrioles comprise the heart of centrosomes, microtubule-organizing centers. To study the function of centrioles in lung and gut development, we genetically disrupted centrioles throughout the mouse endoderm. Surprisingly, removing centrioles from the endoderm did not disrupt intestinal growth or development but blocked lung branching. In the lung, acentriolar SOX2-expressing airway epithelial cells apoptosed. Loss of centrioles activated p53, and removing p53 restored survival of SOX2-expressing cells, lung branching, and mouse viability. To investigate how endodermal p53 activation specifically killed acentriolar SOX2-expressing cells, we assessed ERK, a prosurvival cue. ERK was active throughout the intestine and in the distal lung buds, correlating with tolerance to centriole loss. Pharmacologically inhibiting ERK activated apoptosis in acentriolar cells, revealing that ERK activity protects acentriolar cells from apoptosis. Therefore, centrioles are largely dispensable for endodermal growth and the spatial distribution of ERK activity in the endoderm shapes the developmental consequences of centriolar defects and p53 activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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24. Correction: Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.
- Author
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García-González D, Dumitru I, Zuccotti A, Yen TY, Herranz-Pérez V, Tan LL, Neitz A, García-Verdugo JM, Kuner R, Alfonso J, and Monyer H
- Published
- 2021
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25. A ciliopathy complex builds distal appendages to initiate ciliogenesis.
- Author
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Kumar D, Rains A, Herranz-Pérez V, Lu Q, Shi X, Swaney DL, Stevenson E, Krogan NJ, Huang B, Westlake C, Garcia-Verdugo JM, Yoder BK, and Reiter JF
- Subjects
- Animals, Bacterial Proteins genetics, Bacterial Proteins metabolism, Cell Line, Centrioles pathology, Centrioles ultrastructure, Cilia pathology, Cilia ultrastructure, Ciliopathies metabolism, Ciliopathies pathology, Embryo, Mammalian, Epithelial Cells cytology, Epithelial Cells metabolism, Gene Expression Regulation, Genes, Reporter, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Humans, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins deficiency, Microtubule-Associated Proteins metabolism, Proteins metabolism, Retinal Pigment Epithelium cytology, Retinal Pigment Epithelium metabolism, Signal Transduction, Centrioles metabolism, Cilia metabolism, Ciliopathies genetics, Microtubule-Associated Proteins genetics, Proteins genetics
- Abstract
Cells inherit two centrioles, the older of which is uniquely capable of generating a cilium. Using proteomics and superresolved imaging, we identify a module that we term DISCO (distal centriole complex). The DISCO components CEP90, MNR, and OFD1 underlie human ciliopathies. This complex localizes to both distal centrioles and centriolar satellites, proteinaceous granules surrounding centrioles. Cells and mice lacking CEP90 or MNR do not generate cilia, fail to assemble distal appendages, and do not transduce Hedgehog signals. Disrupting the satellite pools does not affect distal appendage assembly, indicating that it is the centriolar populations of MNR and CEP90 that are critical for ciliogenesis. CEP90 recruits the most proximal known distal appendage component, CEP83, to root distal appendage formation, an early step in ciliogenesis. In addition, MNR, but not CEP90, restricts centriolar length by recruiting OFD1. We conclude that DISCO acts at the distal centriole to support ciliogenesis by restraining centriole length and assembling distal appendages, defects in which cause human ciliopathies., (© 2021 Kumar et al.)
- Published
- 2021
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26. Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.
- Author
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García-González D, Dumitru I, Zuccotti A, Yen TY, Herranz-Pérez V, Tan LL, Neitz A, García-Verdugo JM, Kuner R, Alfonso J, and Monyer H
- Subjects
- Animals, Lateral Ventricles, Mice, Neurons, Olfactory Bulb, Pain, Neurogenesis, Nucleus Accumbens
- Abstract
In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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27. Ultrastructural Characterization of Human Oligodendrocytes and Their Progenitor Cells by Pre-embedding Immunogold.
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Ulloa-Navas MJ, Pérez-Borredá P, Morales-Gallel R, Saurí-Tamarit A, García-Tárraga P, Gutiérrez-Martín AJ, Herranz-Pérez V, and García-Verdugo JM
- Abstract
Oligodendrocytes are the myelinating cells of the central nervous system. They provide trophic, metabolic, and structural support to neurons. In several pathologies such as multiple sclerosis (MS), these cells are severely affected and fail to remyelinate, thereby leading to neuronal death. The gold standard for studying remyelination is the g-ratio, which is measured by means of transmission electron microscopy (TEM). Therefore, studying the fine structure of the oligodendrocyte population in the human brain at different stages through TEM is a key feature in this field of study. Here we study the ultrastructure of oligodendrocytes, its progenitors, and myelin in 10 samples of human white matter using nine different markers of the oligodendrocyte lineage (NG2, PDGFRα, A2B5, Sox10, Olig2, BCAS1, APC-(CC1), MAG, and MBP). Our findings show that human oligodendrocytes constitute a very heterogeneous population within the human white matter and that its stages of differentiation present characteristic features that can be used to identify them by TEM. This study sheds light on how these cells interact with other cells within the human brain and clarify their fine characteristics from other glial cell types., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ulloa-Navas, Pérez-Borredá, Morales-Gallel, Saurí-Tamarit, García-Tárraga, Gutiérrrez-Martín, Herranz-Pérez and Garcia-Verdugo.)
- Published
- 2021
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28. ID4 Is Required for Normal Ependymal Cell Development.
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Rocamonde B, Herranz-Pérez V, Garcia-Verdugo JM, and Huillard E
- Abstract
Ependymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid (CSF) flow and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator ID4 is involved in ependymal cell development and maturation. We observed that Id4 -deficient mice display altered ventricular cell cytoarchitecture, decreased ependymal cell number and enlarged ventricles. In addition, absence of ID4 during embryonic development resulted in decreased ependymal cell number and delayed maturation. Our findings open the way for a potential role of ID4 in ependymal cell development and motor cilia function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rocamonde, Herranz-Pérez, Garcia-Verdugo and Huillard.)
- Published
- 2021
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29. Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission.
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Bentsen MA, Rausch DM, Mirzadeh Z, Muta K, Scarlett JM, Brown JM, Herranz-Pérez V, Baquero AF, Thompson J, Alonge KM, Faber CL, Kaiyala KJ, Bennett C, Pyke C, Ratner C, Egerod KL, Holst B, Meek TH, Kutlu B, Zhang Y, Sparso T, Grove KL, Morton GJ, Kornum BR, García-Verdugo JM, Secher A, Jorgensen R, Schwartz MW, and Pers TH
- Subjects
- Agouti-Related Protein metabolism, Animals, Astrocytes drug effects, Astrocytes metabolism, Blood Glucose analysis, Cell Communication, Cell Nucleus drug effects, Cell Nucleus metabolism, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental etiology, Diabetes Mellitus, Experimental pathology, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 etiology, Diabetes Mellitus, Type 2 pathology, Diet, High-Fat adverse effects, Dietary Sucrose administration & dosage, Dietary Sucrose adverse effects, Humans, Hypothalamus cytology, Hypothalamus pathology, Injections, Intraventricular, Leptin genetics, Male, Melanocortins metabolism, Melanocyte-Stimulating Hormones administration & dosage, Mice, Mice, Knockout, Neurons drug effects, Neurons metabolism, Oligodendroglia drug effects, Oligodendroglia metabolism, RNA-Seq, Receptor, Melanocortin, Type 4 genetics, Receptors, Melanocortin antagonists & inhibitors, Receptors, Melanocortin metabolism, Remission Induction methods, Signal Transduction drug effects, Single-Cell Analysis, Stereotaxic Techniques, Transcriptome drug effects, Diabetes Mellitus, Experimental diet therapy, Diabetes Mellitus, Type 2 drug therapy, Fibroblast Growth Factor 1 administration & dosage, Hypoglycemic Agents administration & dosage, Hypothalamus drug effects, Recombinant Proteins administration & dosage
- Abstract
In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep
ob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.- Published
- 2020
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30. Dynamic Changes in the Neurogenic Potential in the Ventricular-Subventricular Zone of Common Marmoset during Postnatal Brain Development.
- Author
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Akter M, Kaneko N, Herranz-Pérez V, Nakamura S, Oishi H, García-Verdugo JM, and Sawamoto K
- Subjects
- Animals, Brain cytology, Brain growth & development, Callithrix, Cell Movement, Cerebral Ventricles cytology, Cerebral Ventricles growth & development, Hippocampus cytology, Lateral Ventricles cytology, Neocortex cytology, Olfactory Bulb cytology, Spatio-Temporal Analysis, Cell Proliferation, Hippocampus growth & development, Lateral Ventricles growth & development, Neocortex growth & development, Neural Stem Cells cytology, Neurogenesis, Olfactory Bulb growth & development
- Abstract
Even after birth, neuronal production continues in the ventricular-subventricular zone (V-SVZ) and hippocampus in many mammals. The immature new neurons ("neuroblasts") migrate and then mature at their final destination. In humans, neuroblast production and migration toward the neocortex and the olfactory bulb (OB) occur actively only for a few months after birth and then sharply decline with age. However, the precise spatiotemporal profiles and fates of postnatally born neurons remain unclear due to methodological limitations. We previously found that common marmosets, small nonhuman primates, share many features of V-SVZ organization with humans. Here, using marmosets injected with thymidine analogue(s) during various postnatal periods, we demonstrated spatiotemporal changes in neurogenesis during development. V-SVZ progenitor proliferation and neuroblast migration toward the OB and neocortex sharply decreased by 4 months, most strikingly in a V-SVZ subregion from which neuroblasts migrated toward the neocortex. Postnatally born neurons matured within a few months in the OB and hippocampus but remained immature until 6 months in the neocortex. While neurogenic activity was sustained for a month after birth, the distribution and/or differentiation diversity was more restricted in 1-month-born cells than in the neonatal-born population. These findings shed light on distinctive features of postnatal neurogenesis in primates., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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31. Dynamic Changes in Ultrastructure of the Primary Cilium in Migrating Neuroblasts in the Postnatal Brain.
- Author
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Matsumoto M, Sawada M, García-González D, Herranz-Pérez V, Ogino T, Bang Nguyen H, Quynh Thai T, Narita K, Kumamoto N, Ugawa S, Saito Y, Takeda S, Kaneko N, Khodosevich K, Monyer H, García-Verdugo JM, Ohno N, and Sawamoto K
- Subjects
- Animals, Female, Macaca mulatta, Male, Mice, Zebrafish, Cell Movement physiology, Cilia ultrastructure, Lateral Ventricles ultrastructure, Neural Stem Cells ultrastructure, Neurons ultrastructure, Olfactory Bulb ultrastructure
- Abstract
New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in migrating neuroblasts in the postnatal RMS and OB. The primary cilium was observed in migrating neuroblasts in the postnatal RMS and OB in male and female mice and zebrafish, and a male rhesus monkey. Inhibition of intraflagellar transport molecules in migrating neuroblasts impaired their ciliogenesis and rostral migration toward the OB. Serial section transmission electron microscopy revealed that each migrating neuroblast possesses either a pair of centrioles or a basal body with an immature or mature primary cilium. Using immunohistochemistry, live imaging, and serial block-face scanning electron microscopy, we demonstrate that the localization and orientation of the primary cilium are altered depending on the mitotic state, saltatory migration, and deceleration of neuroblasts. Together, our results highlight a close mutual relationship between spatiotemporal regulation of the primary cilium and efficient chain migration of neuroblasts in the postnatal brain. SIGNIFICANCE STATEMENT Immature neurons (neuroblasts) generated in the postnatal brain have a mitotic potential and migrate in chain-like cell aggregates toward the olfactory bulb. Here we report that migrating neuroblasts possess a tiny cellular protrusion called a primary cilium. Immunohistochemical studies with zebrafish, mouse, and monkey brains suggest that the presence of the primary cilium in migrating neuroblasts is evolutionarily conserved. Ciliogenesis in migrating neuroblasts in the rostral migratory stream is suppressed during mitosis and promoted after cell cycle exit. Moreover, live imaging and 3D electron microscopy revealed that ciliary localization and orientation change during saltatory movement of neuroblasts. Our results reveal highly organized dynamics in maturation and positioning of the primary cilium during neuroblast migration that underlie saltatory movement of postnatal-born neuroblasts., (Copyright © 2019 the authors.)
- Published
- 2019
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32. Immunogold Labeling to Detect Streptococcus pyogenes Cas9 in Cell Culture and Tissues by Electron Microscopy.
- Author
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Ulloa-Navas MJ, García-Tárraga P, García-Verdugo JM, and Herranz-Pérez V
- Subjects
- Animals, Brain, CRISPR-Cas Systems immunology, Clustered Regularly Interspaced Short Palindromic Repeats immunology, DNA, Genetic Vectors, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Microscopy, Electron methods, Microscopy, Immunoelectron methods, RNA, Guide, CRISPR-Cas Systems, CRISPR-Associated Protein 9 genetics, Gene Editing methods, Streptococcus pyogenes genetics
- Abstract
The CRISPR-Cas9 system is a powerful and yet precise DNA-editing tool in rapid development. By combining immunogold labeling and electron microscopy with the novel CRISPR-Cas9 system, we propose a new method to gain insight into the biology of this tool. In this study, we analyzed different Cas9-induced systems such as HEK293T cell line, murine oligodendrocyte progenitor cells, brain and liver to detect Cas9 expression by immunoelectron microscopy. Our results show that while Cas9 expression could be found in the nuclei and nucleopores of transfected HEK293T cells, in transfected oligodendrocyte precursor cells, Cas9 was found in cytoplasmic vesicles. In Cas9 constitutively expressing oligodendrocyte precursors, the enzyme was located in the cytoplasm of nondividing cells. Finally, while in the liver Cas9 was detected in different cell types, in the brain we found no specifically labeled cells. In conclusion, immunoelectron microscopy opens a new spectrum of opportunities to study the CRISPR-Cas9 system in a more precise manner.
- Published
- 2019
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33. Immature excitatory neurons develop during adolescence in the human amygdala.
- Author
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Sorrells SF, Paredes MF, Velmeshev D, Herranz-Pérez V, Sandoval K, Mayer S, Chang EF, Insausti R, Kriegstein AR, Rubenstein JL, Manuel Garcia-Verdugo J, Huang EJ, and Alvarez-Buylla A
- Subjects
- Adolescent, Adult, Aged, Basolateral Nuclear Complex cytology, Cell Nucleus genetics, Child, Child, Preschool, Fetus, Hippocampus physiology, Humans, Infant, Infant, Newborn, Male, Middle Aged, Neuronal Plasticity physiology, Sequence Analysis, RNA methods, Single-Cell Analysis methods, Young Adult, Adolescent Development physiology, Basolateral Nuclear Complex growth & development, Neural Stem Cells physiology, Neurogenesis physiology, Neurons physiology
- Abstract
The human amygdala grows during childhood, and its abnormal development is linked to mood disorders. The primate amygdala contains a large population of immature neurons in the paralaminar nuclei (PL), suggesting protracted development and possibly neurogenesis. Here we studied human PL development from embryonic stages to adulthood. The PL develops next to the caudal ganglionic eminence, which generates inhibitory interneurons, yet most PL neurons express excitatory markers. In children, most PL cells are immature (DCX+PSA-NCAM+), and during adolescence many transition into mature (TBR1+VGLUT2+) neurons. Immature PL neurons persist into old age, yet local progenitor proliferation sharply decreases in infants. Using single nuclei RNA sequencing, we identify the transcriptional profile of immature excitatory neurons in the human amygdala between 4-15 years. We conclude that the human PL contains excitatory neurons that remain immature for decades, a possible substrate for persistent plasticity at the interface of the hippocampus and amygdala.
- Published
- 2019
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34. Perineuronal Net Formation during the Critical Period for Neuronal Maturation in the Hypothalamic Arcuate Nucleus.
- Author
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Mirzadeh Z, Alonge KM, Cabrales E, Herranz-Pérez V, Scarlett JM, Brown JM, Hassouna R, Matsen ME, Nguyen HT, Garcia-Verdugo JM, Zeltser LM, and Schwartz MW
- Subjects
- Animals, Arcuate Nucleus of Hypothalamus metabolism, Leptin metabolism, Mice, Mice, Inbred C57BL, Neurons metabolism, Obesity genetics, Obesity metabolism, Arcuate Nucleus of Hypothalamus cytology, Nerve Net, Neurons cytology
- Abstract
In leptin-deficient ob/ob mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC)
1 , a critical brain area for energy and glucose homeostasis2,3 . As this developmental defect can be remedied by systemic leptin administration, but only if given before postnatal day 28, a critical period (CP) for leptin-dependent development of ARC neurocircuits has been proposed4 . In other brain areas, CP closure coincides with the appearance of perineuronal nets (PNNs), extracellular matrix specializations that restrict the plasticity of neurons that they enmesh5 . Here we report that in humans as well as rodents, subsets of neurons in the mediobasal aspect of the ARC are enmeshed by PNN-like structures. In mice, these neurons are densely-packed into a continuous ring that encircles the junction of the ARC and median eminence, which facilitates exposure of ARC neurons to the circulation. Most of the enmeshed neurons are both GABAergic and leptin receptor-positive, including a majority of Agrp neurons. Postnatal formation of the PNN-like structures coincides precisely with closure of the CP for Agrp neuron maturation and is dependent on input from circulating leptin, as postnatal ob/ob mice have reduced ARC PNN-like material that is restored by leptin administration during the CP. We conclude that neurons crucial to metabolic homeostasis are enmeshed by PNN-like structures and organized into a densely packed cluster situated circumferentially at the ARC-ME junction, where metabolically-relevant humoral signals are sensed., Competing Interests: Competing Interests Statement The authors declare no competing financial or non-financial interests in relation to the work described here.- Published
- 2019
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35. Quantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for β-MSH and desacetyl α-MSH in energy homeostasis.
- Author
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Kirwan P, Kay RG, Brouwers B, Herranz-Pérez V, Jura M, Larraufie P, Jerber J, Pembroke J, Bartels T, White A, Gribble FM, Reimann F, Farooqi IS, O'Rahilly S, and Merkle FT
- Subjects
- Chromatography, Liquid, Female, Homeostasis physiology, Humans, Hypothalamus, Leptin metabolism, Male, Mass Spectrometry methods, Neurons metabolism, Neuropeptides metabolism, Pluripotent Stem Cells metabolism, Pro-Opiomelanocortin metabolism, Receptors, Melanocortin metabolism, Tandem Mass Spectrometry, Melanocortins metabolism, alpha-MSH metabolism, beta-MSH metabolism
- Abstract
Objective: The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study was to determine which POMC-derived peptides are present in the human brain, to establish their relative concentrations, and to test if their production is dynamically regulated., Methods: We analysed both fresh post-mortem human hypothalamic tissue and hypothalamic neurons derived from human pluripotent stem cells (hPSCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the sequence and quantify the production of hypothalamic neuropeptides, including those derived from POMC., Results: In both in vitro and in vivo hypothalamic cells, LC-MS/MS revealed the sequence of hundreds of neuropeptides as a resource for the field. Although the existence of β-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl α-MSH (d-α-MSH) were produced in considerable excess of acetylated α-MSH. In hPSC-derived hypothalamic neurons, these POMC derivatives were appropriately trafficked, secreted, and their production was significantly (P < 0.0001) increased in response to the hormone leptin., Conclusions: Our findings challenge the assumed pre-eminence of α-MSH and suggest that in humans, d-α-MSH and β-MSH are likely to be the predominant physiological products acting on melanocortin receptors., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2018
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36. Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain.
- Author
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Fujikake K, Sawada M, Hikita T, Seto Y, Kaneko N, Herranz-Pérez V, Dohi N, Homma N, Osaga S, Yanagawa Y, Akaike T, García-Verdugo JM, Hattori M, Sobue K, and Sawamoto K
- Subjects
- Animals, Brain cytology, Brain growth & development, Cadherins genetics, Catenins metabolism, Cell Adhesion physiology, Cell Movement genetics, Female, Gene Knockdown Techniques, Male, Mice, Nerve Tissue Proteins genetics, Olfactory Bulb cytology, Olfactory Bulb growth & development, Olfactory Bulb physiology, Brain physiology, Neural Stem Cells physiology, Proto-Oncogene Proteins c-fyn physiology
- Abstract
In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB. SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell-cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain., (Copyright © 2018 the authors 0270-6474/18/384599-12$15.00/0.)
- Published
- 2018
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37. Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury.
- Author
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Jinnou H, Sawada M, Kawase K, Kaneko N, Herranz-Pérez V, Miyamoto T, Kawaue T, Miyata T, Tabata Y, Akaike T, García-Verdugo JM, Ajioka I, Saitoh S, and Sawamoto K
- Subjects
- Animals, Animals, Newborn, Cadherins metabolism, Lateral Ventricles pathology, Neuroglia metabolism, Neuroglia ultrastructure, Neurons metabolism, Neurons ultrastructure, rhoA GTP-Binding Protein metabolism, Brain Injuries pathology, Brain Injuries physiopathology, Cell Movement, Neuroglia pathology, Neurons pathology, Recovery of Function
- Abstract
Radial glia (RG) are embryonic neural stem cells (NSCs) that produce neuroblasts and provide fibers that act as a scaffold for neuroblast migration during embryonic development. Although they normally disappear soon after birth, here we found that RG fibers can persist in injured neonatal mouse brains and act as a scaffold for postnatal ventricular-subventricular zone (V-SVZ)-derived neuroblasts that migrate to the lesion site. This injury-induced maintenance of RG fibers has a limited time window during post-natal development and promotes directional saltatory movement of neuroblasts via N-cadherin-mediated cell-cell contacts that promote RhoA activation. Transplanting an N-cadherin-containing scaffold into injured neonatal brains likewise promotes migration and maturation of V-SVZ-derived neuroblasts, leading to functional improvements in impaired gait behaviors. Together these results suggest that RG fibers enable postnatal V-SVZ-derived neuroblasts to migrate toward sites of injury, thereby enhancing neuronal regeneration and functional recovery from neonatal brain injuries., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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38. Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells.
- Author
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Cebrián-Silla A, Alfaro-Cervelló C, Herranz-Pérez V, Kaneko N, Park DH, Sawamoto K, Alvarez-Buylla A, Lim DA, and García-Verdugo JM
- Subjects
- Adult Stem Cells cytology, Animals, Astrocytes cytology, Cell Cycle, Cells, Cultured, Chromatin chemistry, Mice, Lateral Ventricles cytology, Neural Stem Cells cytology, Nuclear Envelope ultrastructure
- Abstract
Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [
3 H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
39. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.
- Author
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Bruel AL, Franco B, Duffourd Y, Thevenon J, Jego L, Lopez E, Deleuze JF, Doummar D, Giles RH, Johnson CA, Huynen MA, Chevrier V, Burglen L, Morleo M, Desguerres I, Pierquin G, Doray B, Gilbert-Dussardier B, Reversade B, Steichen-Gersdorf E, Baumann C, Panigrahi I, Fargeot-Espaliat A, Dieux A, David A, Goldenberg A, Bongers E, Gaillard D, Argente J, Aral B, Gigot N, St-Onge J, Birnbaum D, Phadke SR, Cormier-Daire V, Eguether T, Pazour GJ, Herranz-Pérez V, Goldstein JS, Pasquier L, Loget P, Saunier S, Mégarbané A, Rosnet O, Leroux MR, Wallingford JB, Blacque OE, Nachury MV, Attie-Bitach T, Rivière JB, Faivre L, and Thauvin-Robinet C
- Subjects
- Abnormalities, Multiple genetics, Ciliary Motility Disorders genetics, Encephalocele genetics, Female, Heterozygote, Humans, Male, Mutation genetics, Polycystic Kidney Diseases genetics, Proteins genetics, Retinitis Pigmentosa, Face abnormalities, Orofaciodigital Syndromes genetics
- Abstract
Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes ( C2CD3 , TMEM107 , INTU , KIAA0753 and IFT57 ) and related the clinical spectrum of four genes in other ciliopathies ( C5orf42 , TMEM138 , TMEM231 and WDPCP ) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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40. Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.
- Author
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Torres-Vega E, Mancheño N, Cebrián-Silla A, Herranz-Pérez V, Chumillas MJ, Moris G, Joubert B, Honnorat J, Sevilla T, Vílchez JJ, Dalmau J, Graus F, García-Verdugo JM, and Bataller L
- Subjects
- Adult, Aged, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal genetics, Cell Adhesion Molecules, Neuronal metabolism, DCC Receptor, Electromyography, Female, HEK293 Cells, Humans, Immunoprecipitation, Magnetic Resonance Imaging, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Middle Aged, Muscle, Skeletal pathology, Muscle, Skeletal physiopathology, Myasthenia Gravis complications, Myasthenia Gravis diagnostic imaging, Nerve Growth Factors genetics, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Netrin Receptors, Netrin-1, Neural Cell Adhesion Molecules, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Thymoma complications, Thymoma diagnostic imaging, Thymus Neoplasms complications, Thymus Neoplasms diagnostic imaging, Transfection, Tumor Suppressor Proteins genetics, Autoantibodies blood, Myasthenia Gravis blood, Nerve Growth Factors immunology, Nerve Growth Factors metabolism, Thymoma blood, Thymus Neoplasms blood, Tumor Suppressor Proteins immunology, Tumor Suppressor Proteins metabolism
- Abstract
Objective: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications., Methods: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers)., Results: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma ( p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome ( p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus., Conclusions: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis., Classification of Evidence: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%)., (© 2017 American Academy of Neurology.)
- Published
- 2017
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41. An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling.
- Author
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Nager AR, Goldstein JS, Herranz-Pérez V, Portran D, Ye F, Garcia-Verdugo JM, and Nachury MV
- Subjects
- Actins metabolism, Animals, Cell Line, Humans, Kidney cytology, Kidney metabolism, Mice, Microscopy, Electron, Scanning, Receptors, Somatostatin metabolism, Signal Transduction, Cilia metabolism, Extracellular Vesicles metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
Signaling receptors dynamically exit cilia upon activation of signaling pathways such as Hedgehog. Here, we find that when activated G protein-coupled receptors (GPCRs) fail to undergo BBSome-mediated retrieval from cilia back into the cell, these GPCRs concentrate into membranous buds at the tips of cilia before release into extracellular vesicles named ectosomes. Unexpectedly, actin and the actin regulators drebrin and myosin 6 mediate ectosome release from the tip of cilia. Mirroring signal-dependent retrieval, signal-dependent ectocytosis is a selective and effective process that removes activated signaling molecules from cilia. Congruently, ectocytosis compensates for BBSome defects as ectocytic removal of GPR161, a negative regulator of Hedgehog signaling, permits the appropriate transduction of Hedgehog signals in Bbs mutants. Finally, ciliary receptors that lack retrieval determinants such as the anorexigenic GPCR NPY2R undergo signal-dependent ectocytosis in wild-type cells. Our data show that signal-dependent ectocytosis regulates ciliary signaling in physiological and pathological contexts., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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42. Characterization of multiciliated ependymal cells that emerge in the neurogenic niche of the aged zebrafish brain.
- Author
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Ogino T, Sawada M, Takase H, Nakai C, Herranz-Pérez V, Cebrián-Silla A, Kaneko N, García-Verdugo JM, and Sawamoto K
- Subjects
- Aging pathology, Animals, Animals, Genetically Modified, Cell Movement physiology, Cilia ultrastructure, Ependyma growth & development, Ependyma physiology, Ependyma ultrastructure, Immunohistochemistry, Microscopy, Confocal, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Telencephalon growth & development, Telencephalon physiology, Telencephalon ultrastructure, Zebrafish anatomy & histology, Zebrafish growth & development, Aging physiology, Ependyma cytology, Stem Cell Niche physiology, Telencephalon cytology, Zebrafish physiology
- Abstract
In mammals, ventricular walls of the developing brain maintain a neurogenic niche, in which radial glial cells act as neural stem cells (NSCs) and generate new neurons in the embryo. In the adult brain, the neurogenic niche is maintained in the ventricular-subventricular zone (V-SVZ) of the lateral wall of lateral ventricles and the hippocampal dentate gyrus. In the neonatal V-SVZ, radial glial cells transform into astrocytic postnatal NSCs and multiciliated ependymal cells. On the other hand, in zebrafish, radial glial cells continue to cover the surface of the adult telencephalic ventricle and maintain a higher neurogenic potential in the adult brain. However, the cell composition of the neurogenic niche of the aged zebrafish brain has not been investigated. Here we show that multiciliated ependymal cells emerge in the neurogenic niche of the aged zebrafish telencephalon. These multiciliated cells appear predominantly in the dorsal part of the ventral telencephalic ventricular zone, which also contains clusters of migrating new neurons. Scanning electron microscopy and live imaging analyses indicated that these multiple cilia beat coordinately and generate constant fluid flow within the ventral telencephalic ventricle. Analysis of the cell composition by transmission electron microscopy revealed that the neurogenic niche in the aged zebrafish contains different types of cells, with ultrastructures similar to those of ependymal cells, transit-amplifying cells, and migrating new neurons in postnatal mice. These data suggest that the transformation capacity of radial glial cells is conserved but that its timing is different between fish and mice. J. Comp. Neurol. 524:2982-2992, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
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43. Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease.
- Author
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Bonet-Costa V, Herranz-Pérez V, Blanco-Gandía M, Mas-Bargues C, Inglés M, Garcia-Tarraga P, Rodriguez-Arias M, Miñarro J, Borras C, Garcia-Verdugo JM, and Viña J
- Subjects
- Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Astrocytes drug effects, Astrocytes metabolism, Avoidance Learning drug effects, Bexarotene, Brain diagnostic imaging, Brain drug effects, Brain metabolism, Brain pathology, Cells, Cultured, Disease Models, Animal, Female, Habituation, Psychophysiologic drug effects, Maze Learning, Mice, Inbred C57BL, Mice, Transgenic, Neuroprotective Agents pharmacology, Olfactory Perception drug effects, Plaque, Amyloid diagnostic imaging, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Recognition, Psychology drug effects, Tetrahydronaphthalenes pharmacology, Alzheimer Disease drug therapy, Amyloid beta-Peptides metabolism, Apolipoproteins E metabolism, Genistein pharmacology, Nootropic Agents pharmacology, PPAR gamma metabolism
- Abstract
Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer's disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.
- Published
- 2016
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44. Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium.
- Author
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Ohata S, Herranz-Pérez V, Nakatani J, Boletta A, García-Verdugo JM, and Álvarez-Buylla A
- Subjects
- Animals, Ependyma cytology, Ependyma metabolism, Ependymoglial Cells cytology, Mice, Mice, Knockout, TRPP Cation Channels metabolism, Cell Polarity genetics, Cerebral Ventricles metabolism, Cilia metabolism, Ependymoglial Cells metabolism, TRPP Cation Channels genetics
- Abstract
Directional beating of ependymal (E) cells' cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin-Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells' apical area. Analyses of single- and double-heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells' PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus., Significance Statement: This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location-specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs' primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus., (Copyright © 2015 the authors 0270-6474/15/3511153-16$15.00/0.)
- Published
- 2015
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45. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain.
- Author
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Paradells S, Rocamonde B, Llinares C, Herranz-Pérez V, Jimenez M, Garcia-Verdugo JM, Zipancic I, Soria JM, and Garcia-Esparza MA
- Subjects
- Animals, Astrocytes drug effects, Cell Differentiation drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Lateral Ventricles pathology, Lateral Ventricles ultrastructure, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Neural Stem Cells drug effects, Neuroglia drug effects, Lateral Ventricles drug effects, Mycotoxins toxicity, Ochratoxins toxicity
- Abstract
Ochratoxin A (OTA), a mycotoxin that was discovered as a secondary metabolite of the fungal species Aspergillus and Penicillium, is a common contaminant in food and animal feed. This mycotoxin has been described as teratogenic, carcinogenic, genotoxic, immunotoxic and has been proven a potent neurotoxin. Other authors have previously reported the effects of OTA in different structures of the central nervous system as well as in some neurogenic regions. However, the impact of OTA exposure in the subventricular zone (SVZ) has not been assessed yet. To elucidate whether OTA affects neural precursors of the mouse SVZ we investigated, in vitro and in vivo, the effects of OTA exposure on the SVZ and on the neural precursors obtained from this neurogenic niche. In this work, we prove the cumulative effect of OTA exposure on proliferation, differentiation and depletion of neural stem cells cultured from the SVZ. In addition, we corroborated these results in vivo by immunohistochemistry and electron microscopy. As a result, we found a significant alteration in the proliferation process, which was evidenced by a decrease in the number of 5-bromo-2-deoxyuridine-positive cells and glial cells, as well as, a significant decrease in the number of neuroblasts in the SVZ. To summarize, in this study we demonstrate how OTA could be a threat to the developing and the adult SVZ through its impact in cell viability, proliferation and differentiation in a dose-dependent manner., (Copyright © 2014 John Wiley & Sons, Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
46. Long-term hydrocephalus alters the cytoarchitecture of the adult subventricular zone.
- Author
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Campos-Ordoñez T, Herranz-Pérez V, Chaichana KL, Rincon-Torroella J, Rigamonti D, García-Verdugo JM, Quiñones-Hinojosa A, and Gonzalez-Perez O
- Subjects
- Adult, Animals, Cohort Studies, Corpus Callosum metabolism, Corpus Callosum pathology, Disease Models, Animal, Doublecortin Domain Proteins, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein metabolism, Humans, Hydrocephalus physiopathology, Internal Capsule metabolism, Internal Capsule pathology, Ki-67 Antigen metabolism, Lateral Ventricles ultrastructure, Magnetic Resonance Imaging, Male, Maze Learning physiology, Mice, Mice, Inbred BALB C, Microtubule-Associated Proteins metabolism, Neuropeptides metabolism, Time Factors, Young Adult, Hydrocephalus pathology, Lateral Ventricles metabolism, Lateral Ventricles pathology
- Abstract
Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n=18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age>18years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the subventricular niche as well as the width of corpus callosum and internal capsule., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
47. Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus.
- Author
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Ohata S, Nakatani J, Herranz-Pérez V, Cheng J, Belinson H, Inubushi T, Snider WD, García-Verdugo JM, Wynshaw-Boris A, and Alvarez-Buylla A
- Subjects
- Animals, Cell Polarity genetics, Cilia genetics, Dishevelled Proteins, Hydrocephalus genetics, Hydrocephalus pathology, Mice, Mice, Transgenic, Signal Transduction genetics, Adaptor Proteins, Signal Transducing genetics, Cell Polarity physiology, Cilia pathology, Ependyma pathology, Hydrocephalus etiology, Phosphoproteins genetics, Signal Transduction physiology
- Abstract
Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
- Author
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Thauvin-Robinet C, Lee JS, Lopez E, Herranz-Pérez V, Shida T, Franco B, Jego L, Ye F, Pasquier L, Loget P, Gigot N, Aral B, Lopes CA, St-Onge J, Bruel AL, Thevenon J, González-Granero S, Alby C, Munnich A, Vekemans M, Huet F, Fry AM, Saunier S, Rivière JB, Attié-Bitach T, Garcia-Verdugo JM, Faivre L, Mégarbané A, and Nachury MV
- Subjects
- Cell Line, Child, Preschool, Genetic Predisposition to Disease, HEK293 Cells, Humans, Male, Microcephaly genetics, Proteins genetics, Centrioles genetics, Microtubule-Associated Proteins genetics, Orofaciodigital Syndromes genetics
- Abstract
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.
- Published
- 2014
- Full Text
- View/download PDF
49. NIR excitation of upconversion nanohybrids containing a surface grafted Bodipy induces oxygen-mediated cancer cell death.
- Author
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González-Béjar M, Liras M, Francés-Soriano L, Voliani V, Herranz-Pérez V, Duran-Moreno M, Garcia-Verdugo JM, Alarcon EI, Scaiano JC, and Pérez-Prieto J
- Abstract
We report the preparation of water-dispersible, ca. 30 nm-sized nanohybrids containing NaYF
4 :Er3+ , Yb3+ up-conversion nanoparticles (UCNPs), capped with a polyethylene glycol (PEG) derivative and highly loaded with a singlet oxygen photosensitizer, specifically a diiodo-substituted Bodipy (IBDP). The photosensitizer, bearing a carboxylic group, was anchored to the UCNP surface and, at the same time, embedded in the PEG capping; the combined action of the UCNP surface and PEG facilitated the loading for an effective energy transfer and, additionally, avoided photosensitizer leaching from the nanohybrid (UCNP-IBDP@PEG). The effectiveness of the nanohybrids in generating singlet oxygen after near-infrared (NIR) excitation (975 nm) with a continuous wavelength (CW) laser was evidenced by using a probe molecule. In vitro assays demonstrated that the UCNP-IBDP@PEG nanohybrid was taken up by the SH-SY5Y human neuroblastoma-derived cells showing low cytotoxicity. Moreover, ca. 50% cancer cell death was observed after NIR irradiation (45 min, 239 mW).- Published
- 2014
- Full Text
- View/download PDF
50. Orthogonal functionalisation of upconverting NaYF4 nanocrystals.
- Author
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Voliani V, González-Béjar M, Herranz-Pérez V, Duran-Moreno M, Signore G, Garcia-Verdugo JM, and Pérez-Prieto J
- Subjects
- Molecular Structure, Fluorides chemistry, Nanoparticles chemistry, Polyethylene Glycols chemistry, Succinimides chemistry, Yttrium chemistry
- Abstract
A simple and straightforward method for the orthogonal functionalisation of upconverting NaYF4 nanocrystals (UCNCs)-doped withYb(3+) and Er(3+)-based on N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) selective reactions between two dyes and two different reactive groups present at the periphery of the upconverting nanocrystals is reported. Organic-soluble UCNCs of 10 and 50 nm in size are encapsulated efficiently in a 1:1 mixture of two commercial 3000 Da poly(ethylene glycol) derivatives with two different reactive groups (amino and carboxylic groups). The water-dispersible UCNCs are non-cytotoxic, stable in the physiological environment, and present free amine and carboxylic reactive groups on their periphery, allowing rapid, selective, and modular covalent conjugation to payloads through EDC/NHS reactions. PEG-encapsulated UCNCs with and without covalent conjugation to payloads are characterised in vitro through spectroscopic, dynamic light scattering, and electron microscopy measurements. Living cell analyses coupled with TEM measurements confirm the uptake and low cytotoxicity of the coated UCNCs. They are linked covalently to two different dyes, internalised by living cells, and analysed by confocal microscopy. The related colocalisation measurements prove the reactivity of both amines and carboxylic acids on the periphery of the nanocrystals. This approach demonstrates that it is possible to produce water-dispersible and cyto-compatible dual-functional UCNCs., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
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