15 results on '"Gridley, Thomas"'
Search Results
2. Parent stem cells can serve as niches for their daughter cells
- Author
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Pardo-Saganta, Ana, Tata, Purushothama Rao, Law, Brandon M., Saez, Borja, Chow, Ryan Dz-Wei, Prabhu, Mythili, Gridley, Thomas, and Rajagopal, Jayaraj
- Subjects
Hematopoietic stem cells ,Cell differentiation ,Mammals ,Environmental issues ,Science and technology ,Zoology and wildlife conservation ,Harvard University. Harvard Stem Cell Institute - Abstract
Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance (1, 2), while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation (3-6). Recently, stem cells have been shown to regulate themselves using an autocrine mechanism (7). The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells (1). Since then, an increasing body of work has focused on defining stem cell niches (1-6). Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells (8, 9). Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells (9, 10). Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche., To establish whether post-mitotic ciliated cells send a conventional feedback signal to regulate the replication of their parent stem and progenitor cells, we genetically ablated ciliated cells using FOXJ1-creER; LSL-DTA [...]
- Published
- 2015
3. Notch signal reception is required in vascular smooth muscle cells for ductus arteriosus closure
- Author
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Krebs, Luke T., Norton, Christine R., and Gridley, Thomas
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Receptors, Notch ,Calcium-Binding Proteins ,Membrane Proteins ,Ductus Arteriosus ,Article ,Muscle, Smooth, Vascular ,Mice ,embryonic structures ,cardiovascular system ,Animals ,Intercellular Signaling Peptides and Proteins ,Serrate-Jagged Proteins ,cardiovascular diseases ,Jagged-1 Protein ,Signal Transduction - Abstract
The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus, and is one of the most common congenital heart defects. Our previous work demonstrated that vascular smooth muscle cell expression of the Jag1 gene, which encodes a ligand for Notch family receptors, is essential for postnatal closure of the ductus arteriosus in mice. However, it was not known what cell population was responsible for receiving the Jag1-mediated signal. Here we show, using smooth muscle cell-specific deletion of the Rbpj gene, which encodes a transcription factor that mediates all canonical Notch signaling, that Notch signal reception in the vascular smooth muscle cell compartment is required for ductus arteriosus closure. These data indicate that homotypic vascular smooth muscle cell interactions are required for proper contractile smooth muscle cell differentiation and postnatal closure of the ductus arteriosus in mice.
- Published
- 2016
4. Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates.
- Author
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Basch, Martin L., Brown II, Rogers M., Jen, Hsin-I, Semerci, Fatih, Depreux, Frederic, Edlund, Renée K., Hongyuan Zhang, Norton, Christine R., Gridley, Thomas, Cole, Susan E., Doetzlhofer, Angelika, Maletic-Savatic, Mirjana, Segil, Neil, and Groves, Andrew K.
- Published
- 2016
- Full Text
- View/download PDF
5. DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1.
- Author
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Rostama, Bahman, Turner, Jacqueline E., Seavey, Guy T., Norton, Christine R., Gridley, Thomas, Vary, Calvin P. H., and Liaw, Lucy
- Published
- 2015
- Full Text
- View/download PDF
6. Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium.
- Author
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Horvay, Katja, Jardé, Thierry, Casagranda, Franca, Perreau, Victoria M, Haigh, Katharina, Nefzger, Christian M, Akhtar, Reyhan, Gridley, Thomas, Berx, Geert, Haigh, Jody J, Barker, Nick, Polo, Jose M, Hime, Gary R, and Abud, Helen E
- Subjects
SNAILS ,STEM cells ,EPITHELIAL cells ,INTESTINAL cancer ,APOPTOSIS ,KNOCKOUT mice - Abstract
Snail family members regulate epithelial-to-mesenchymal transition ( EMT) during invasion of intestinal tumours, but their role in normal intestinal homeostasis is unknown. Studies in breast and skin epithelia indicate that Snail proteins promote an undifferentiated state. Here, we demonstrate that conditional knockout of Snai1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells and bias towards differentiation of secretory lineages. In vitro organoid cultures derived from Snai1 conditional knockout mice also undergo apoptosis when Snai1 is deleted. Conversely, ectopic expression of Snai1 in the intestinal epithelium in vivo results in the expansion of the crypt base columnar cell pool and a decrease in secretory enteroendocrine and Paneth cells. Following conditional deletion of Snai1, the intestinal epithelium fails to produce a proliferative response following radiation-induced damage indicating a fundamental requirement for Snai1 in epithelial regeneration. These results demonstrate that Snai1 is required for regulation of lineage choice, maintenance of CBC stem cells and regeneration of the intestinal epithelium following damage. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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7. Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis.
- Author
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Mase, Shun, Shitamukai, Atsunori, Wu, Quan, Morimoto, Mitsuru, Gridley, Thomas, and Matsuzaki, Fumio
- Subjects
- *
NEUROGLIA , *NEURAL stem cells , *NOTCH genes , *DEVELOPMENTAL neurobiology , *MICE - Abstract
[Display omitted] • Notch signaling is essential to maintain radial glial cells (RGCs). • The functional relationship between Notch1 and Notch2 in RGCs is elusive. • Notch1 knockout affected RGC maintenance in early to mid-neurogenesis. • Notch1 and Notch2 function together for RGC maintenance in late neurogenesis. During mammalian corticogenesis, Notch signaling is essential to maintain neural stem cells called radial glial cells (RGCs) and the cortical architecture. Because the conventional knockout of either Notch1 or Notch2 causes a neuroepithelial loss prior to neurogenesis, their functional relationship in RGCs remain elusive. Here, we investigated the impacts of single knockout of Notch1 and Notch2 genes, and their conditional double knockout (DKO) on mouse corticogenesis. We demonstrated that Notch1 single knockout affected RGC maintenance in early to mid-neurogenesis whereas Notch2 knockout caused no apparent defect. In contrast, Notch2 plays a role in the RGC maintenance as Notch1 does at the late stage. Notch1 and Notch2 DKO resulted in the complete loss of RGCs, suggesting their cooperative function. We found that Notch activity in RGCs depends on the Notch gene dosage irrespective of Notch1 or Notch2 at late neurogenic stage, and that Notch1 and Notch2 have a similar activity, most likely due to a drastic increase in Notch 2 transcription. Our results revealed that Notch1 has an essential role in establishing the RGC pool during the early stage, whereas Notch1 and Notch2 subsequently exhibit a comparable function for RGC maintenance and neurogenesis in the late neurogenic period in the mouse telencephalon. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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8. DIO3 protects against thyrotoxicosis-derived cranio-encephalic and cardiac congenital abnormalities.
- Author
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Martinez ME, Pinz I, Preda M, Norton CR, Gridley T, and Hernandez A
- Subjects
- Humans, Pregnancy, Female, Animals, Mice, Iodide Peroxidase genetics, Iodide Peroxidase metabolism, Mice, Inbred C57BL, Thyroid Hormones, Brain metabolism, Choanal Atresia, Cleft Palate, Thyrotoxicosis complications, Hyperthyroidism, Heart Defects, Congenital
- Abstract
Maternal hyperthyroidism is associated with an increased incidence of congenital abnormalities at birth, but it is not clear which of these defects arise from a transient developmental excess of thyroid hormone and which depend on pregnancy stage, antithyroid drug choice, or unwanted subsequent fetal hypothyroidism. To address this issue, we studied a mouse model of comprehensive developmental thyrotoxicosis secondary to a lack of type 3 deiodinase (DIO3). Dio3-/- mice exhibited reduced neonatal viability on most genetic backgrounds and perinatal lethality on a C57BL/6 background. Dio3-/- mice exhibited severe growth retardation during the neonatal period and cartilage loss. Mice surviving after birth manifested brain and cranial dysmorphisms, severe hydrocephalus, choanal atresia, and cleft palate. These abnormalities were noticeable in C57BL/6J Dio3-/- mice at fetal stages, in addition to a thyrotoxic heart with septal defects and thin ventricular walls. Our findings stress the protecting role of DIO3 during development and support the hypothesis that human congenital abnormalities associated with hyperthyroidism during pregnancy are caused by transient thyrotoxicosis before clinical intervention. Our results also suggest thyroid hormone involvement in the etiology of idiopathic pathologies including cleft palate, choanal atresia, Chiari malformations, Kaschin-Beck disease, and Temple and other cranio-encephalic and heart syndromes.
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- 2022
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9. Mouse models of development and disease: Preface.
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Gridley T and Oxburgh L
- Subjects
- Animals, Mice, Disease Models, Animal
- Published
- 2022
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10. Mouse mutagenesis and phenotyping to generate models of development and disease.
- Author
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Gridley T and Murray SA
- Subjects
- Animals, Male, Mammals genetics, Mice, Mutagenesis genetics, Genome, Spermatozoa
- Abstract
For many years, the laboratory mouse has been the favored model organism to study mammalian development, biology and disease. Among its advantages for these studies are its close concordance with human biology, the syntenic relationship between the mouse and other mammalian genomes, the existence of many inbred strains, its short gestation period, its relatively low cost for housing and husbandry, and the wide array of tools for genome modification, mutagenesis, and for cryopreserving embryos, sperm and eggs. The advent of CRISPR genome modification techniques has considerably broadened the landscape of model organisms available for study, including other mammalian species. However, the mouse remains the most popular and utilized system to model human development, biology, and disease processes. In this review, we will briefly summarize the long history of mice as a preferred mammalian genetic and model system, and review current large-scale mutagenesis efforts using genome modification to produce improved models for mammalian development and disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
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11. Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression.
- Author
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Blanco-Gómez A, Hontecillas-Prieto L, Corchado-Cobos R, García-Sancha N, Salvador N, Castellanos-Martín A, Sáez-Freire MDM, Mendiburu-Eliçabe M, Alonso-López D, De Las Rivas J, Lorente M, García-Casas A, Del Carmen S, Abad-Hernández MDM, Cruz-Hernández JJ, Rodríguez-Sánchez CA, Claros-Ampuero J, García-Cenador B, García-Criado J, Orimo A, Gridley T, Pérez-Losada J, and Castillo-Lluva S
- Subjects
- Animals, Breast Neoplasms metabolism, Breast Neoplasms mortality, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Knockout, Receptor, ErbB-2 genetics, Snail Family Transcription Factors genetics, Stromal Cells metabolism, Tumor Microenvironment, Xenograft Model Antitumor Assays, Breast Neoplasms pathology, Receptor, ErbB-2 metabolism, Snail Family Transcription Factors metabolism, Stromal Cells pathology
- Abstract
SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2
+ /ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2 -deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+ /ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+ /ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+ /ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. SIGNIFICANCE: Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2+ breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5216/F1.large.jpg., (©2020 American Association for Cancer Research.)- Published
- 2020
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12. Notch Dosage : Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.
- Author
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Blackwood CA, Bailetti A, Nandi S, Gridley T, and Hébert JM
- Abstract
Neural stem cells in the lateral ganglionic eminence (LGE) generate progenitors that migrate through the rostral migratory stream (RMS) to repopulate olfactory bulb (OB) interneurons, but the regulation of this process is poorly defined. The evolutionarily conserved Notch pathway is essential for neural development and maintenance of neural stem cells. Jagged1, a Notch ligand, is required for stem cell maintenance. In humans, heterozygous mutations in JAGGED1 cause Alagille syndrome, a genetic disorder characterized by complications such as cognitive impairment and reduced number of bile ducts in the liver, suggesting the presence of a JAGGED1 haploinsufficient phenotype. Here, we examine the role of Jagged1 using a conditional loss-of-function allele in the nervous system. We show that heterozygous Jagged1 mice possess a haploinsufficient phenotype that is associated with a reduction in size of the LGE, a reduced proliferative state, and fewer progenitor cells in the LGE and RMS. Moreover, loss of Jagged1 leads to deficits in periglomerular interneurons in the OB. Our results support a dose-dependent role for Jagged1 in maintaining progenitor division within the LGE and RMS., (Copyright © 2020 Blackwood, Bailetti, Nandi, Gridley and Hébert.)
- Published
- 2020
- Full Text
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13. Notch signal reception is required in vascular smooth muscle cells for ductus arteriosus closure.
- Author
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Krebs LT, Norton CR, and Gridley T
- Subjects
- Animals, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Jagged-1 Protein, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Muscle, Smooth, Vascular cytology, Serrate-Jagged Proteins, Ductus Arteriosus embryology, Muscle, Smooth, Vascular embryology, Muscle, Smooth, Vascular metabolism, Receptors, Notch metabolism, Signal Transduction
- Abstract
The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus, and is one of the most common congenital heart defects. Our previous work demonstrated that vascular smooth muscle cell expression of the Jag1 gene, which encodes a ligand for Notch family receptors, is essential for postnatal closure of the ductus arteriosus in mice. However, it was not known what cell population was responsible for receiving the Jag1-mediated signal. Here we show, using smooth muscle cell-specific deletion of the Rbpj gene, which encodes a transcription factor that mediates all canonical Notch signaling, that Notch signal reception in the vascular smooth muscle cell compartment is required for ductus arteriosus closure. These data indicate that homotypic vascular smooth muscle cell interactions are required for proper contractile smooth muscle cell differentiation and postnatal closure of the ductus arteriosus in mice., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
14. Twenty Years in Maine: Integrating Insights from Developmental Biology into Translational Medicine in a Small State.
- Author
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Gridley T
- Subjects
- Animals, Humans, Maine, Mice, Patient-Centered Care, Time Factors, Developmental Biology, Precision Medicine, Translational Research, Biomedical
- Abstract
In this chapter, I give my personal reflections on more than 30 years of studying developmental biology in the mouse model, spending 20 of those years doing research in Maine, a small rural state. I also give my thoughts on my recent experience transitioning to a large medical center in Maine, and the issues involved with integrating insights from developmental biology and regenerative medicine into the fabric of translational and clinical patient care in such an environment., (© 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
15. DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1.
- Author
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Rostama B, Turner JE, Seavey GT, Norton CR, Gridley T, Vary CP, and Liaw L
- Subjects
- Activin Receptors, Type II genetics, Activin Receptors, Type II metabolism, Adaptor Proteins, Signal Transducing, Animals, Aorta metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Calcium-Binding Proteins, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Proliferation, Cells, Cultured, Coronary Vessels metabolism, Cyclin-Dependent Kinase Inhibitor p27 genetics, Genotype, Growth Differentiation Factor 2, Humans, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Lung blood supply, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Inbred C57BL, Mice, Knockout, Phenotype, RNA Interference, Receptor, Notch1 genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Signal Transduction, Smad Proteins, Receptor-Regulated genetics, Smad Proteins, Receptor-Regulated metabolism, Thrombospondin 1 genetics, Transfection, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Endothelial Cells metabolism, Growth Differentiation Factors metabolism, Intercellular Signaling Peptides and Proteins metabolism, Receptor, Notch1 metabolism, Thrombospondin 1 metabolism
- Abstract
Objective: Bone morphogenetic protein-9 (BMP9)/activin-like kinase-1 and delta-like 4 (DLL4)/Notch promote endothelial quiescence, and we aim to understand mechanistic interactions between the 2 pathways. We identify new targets that contribute to endothelial quiescence and test whether loss of Dll4(+/-) in adult vasculature alters BMP signaling., Approach and Results: Human endothelial cells respond synergistically to BMP9 and DLL4 stimulation, showing complete quiescence and induction of HEY1 and HEY2. Canonical BMP9 signaling via activin-like kinase-1-Smad1/5/9 was disrupted by inhibition of Notch signaling, even in the absence of exogenous DLL4. Similarly, DLL4 activity was suppressed when the basal activin-like kinase-1-Smad1/5/9 pathway was inhibited, showing that these pathways are interdependent. BMP9/DLL4 required induction of P27(KIP1) for quiescence, although multiple factors are involved. To understand these mechanisms, we used proteomics data to identify upregulation of thrombospondin-1, which contributes to the quiescence phenotype. To test whether Dll4 regulates BMP/Smad pathways and endothelial cell phenotype in vivo, we characterized the vasculature of Dll4(+/-) mice, analyzing endothelial cells in the lung, heart, and aorta. Together with changes in endothelial structure and vascular morphogenesis, we found that loss of Dll4 was associated with a significant upregulation of pSmad1/5/9 signaling in lung endothelial cells. Because steady-state endothelial cell proliferation rates were not different in the Dll4(+/-) mice, we propose that the upregulation of pSmad1/5/9 signaling compensates to maintain endothelial cell quiescence in these mice., Conclusions: DLL4/Notch and BMP9/activin-like kinase-1 signaling rely on each other's pathways for full activity. This represents an important mechanism of cross talk that enhances endothelial quiescence and sensitively coordinates cellular responsiveness to soluble and cell-tethered ligands., (© 2015 American Heart Association, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
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