185 results on '"Galjart N"'
Search Results
2. Microtubule plus-end tracking protein CLASP2 KO mice phenocopy CAMT: a role for CLASP2 in hematopoiesis and hematopoietic stem cell maintenance: PA 2.04–1
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Gutierrez, L, Drabek, D, Robin, C, Galjart, N, Vermeij, M, Clapes, T, Patel, S R, Boisset, J-C, Van Haren, J, Pereira, A L, Liu, Z, Akinci, U, Nikolic, T, Van Ijcken, W, Van Den Hout, M, Meinders, M, Melo, C, Sambade, C, Drabek, K, Hendriks, R W, Philipsen, S, Mommaas, M, Grosveld, F, Maiato, H, and Italiano, J E
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- 2013
3. Within-strain variation in behavior differs consistently between common inbred strains of mice
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Loos, M., Koopmans, B., Aarts, E., Maroteaux, G., van der Sluis, S., Verhage, M., Smit, A.B., Brussaard, A.B., Borst, J.G.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Spruijt, B.M., de Zeeuw, C.I., General Practice, Erasmus MC other, Cognitive and Systems Neuroscience (SILS, FNWI), Netherlands Institute for Neuroscience (NIN), Human genetics, NCA - Brain mechanisms in health and disease, Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Functional Genomics, Complex Trait Genetics, and Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease
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Male ,Genotype ,Biology ,Inbred C57BL ,Genetic Heterogeneity ,Mice ,Inbred strain ,Species Specificity ,Mice, Inbred NOD ,Genetics ,Animals ,Inbred DBA ,Gene–environment interaction ,Inbred BALB C ,Mice, Inbred BALB C ,Behavior ,Behavior, Animal ,Genetic heterogeneity ,Animal ,Robustness (evolution) ,Phenotype ,Human genetics ,Mice, Inbred C57BL ,Behavioral test ,Mice, Inbred DBA ,Inbred NOD ,Gene-Environment Interaction - Abstract
Genetic and environmental factors interact throughout life and give rise to individual differences, i.e., individuality. The diversifying effect of environmental factors is counteracted by genetic mechanisms to yield persistence of specific features (robustness). Here, we compared robustness between cohorts of isogenic mice of eight different commonly used strains by analyzing to what extent environmental variation contributed to individuality in each of the eight genotypes, using a previously published dataset. Behavior was assessed in the home-cage, providing control over environmental factors, to reveal within-strain variability in numerous spontaneous behaviors. Indeed, despite standardization and in line with previous studies, substantial variability among mice of the same inbred strain was observed. Strikingly, across a multidimensional set of 115 behavioral parameters, several strains consistently ranked high in within-strain variability (DBA/2J, 129S1/Sv A/J and NOD/LtJ), whereas other strains ranked low (C57BL/6J and BALB/c). Strain rankings of within-strain variability in behavior were confirmed in an independent, previously published behavioral dataset using conventional behavioral tests administered to different mice from the same breeding colonies. Together, these show that genetically inbred mouse strains consistently differ in phenotypic robustness against environmental variation, suggesting that genetic factors contribute to variation in robustness.
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- 2015
4. Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3ß (GSK3ß)-dependent phosphorylation and the level of CLIP-associated protein 2 (CLASP2) mediating the capture of
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Basu S, Sladecek S, Pemble H, Wittmann T, Slotman JA, van Cappellen W, Brenner HR, and Galjart N
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animal structures ,macromolecular substances ,musculoskeletal system - Abstract
he postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2 a MT plus end tracking protein (+TIP) increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters are not yet understood. To examine this we used myotubes cultured on agrin patches that induce AChR clustering in a two dimensional manner. We show that expression of a CLASP2 mutant in which the nine GSK3 target serines are mutated to alanine (CLASP2–9XS/9XA) and are resistant to GSK3ß dependent phosphorylation promotes MT capture at clusters and increases AChR cluster size compared with myotubes that express similar levels of wild type CLASP2 or that are noninfected. Conversely myotubes expressing a phosphomimetic form of CLASP2 (CLASP2–8XS/D) show enrichment of immobile mutant CLASP2 in clusters but MT capture and AChR cluster size are reduced. Taken together our data suggest that both GSK3ß dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus ends.
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- 2014
5. P470Microtubule plus-end tracking protein complex: a novel pharmacological target for modulating Nav1.5 trafficking and function
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Marchal, G A, primary, Portero, V, additional, Casini, S, additional, Verkerk, A O, additional, Galjart, N, additional, and Remme, C A, additional
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- 2018
- Full Text
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6. The Complex of β-Galactosidase, Neuraminidase and 'Protective Protein' in Lysosomes: Molecular Characterization of the 'Protective Protein'
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D’Azzo, A., Gillemans, N., Galjart, N., Azzi, Angelo, editor, Drahota, Zdenek, editor, and Papa, Sergio, editor
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- 1989
- Full Text
- View/download PDF
7. Activity and impulsive action are controlled by different genetic and environmental factors
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Loos, M., van der Sluis, S., Bochdanovits, Z., van Zutphen, I.J., Pattij, T., Stiedl, O., Brussaard, A.B., Borst, J.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., Spijker, S., Netherlands Institute for Neuroscience (NIN), Molecular and Cellular Neurobiology, Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam - Addictive Behavior, Human genetics, Anatomy and neurosciences, NCA - Addictive Behavior, and Cognitive and Systems Neuroscience (SILS, FNWI)
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Male ,Serial reaction time ,Elevated plus maze ,Genotype ,Vesicular Transport Proteins ,Prefrontal Cortex ,Environment ,Motor Activity ,Impulsivity ,Genetic correlation ,Open field ,Developmental psychology ,Correlation ,Mice ,Behavioral Neuroscience ,SDG 3 - Good Health and Well-being ,Reaction Time ,Genetics ,medicine ,Animals ,Prefrontal cortex ,Sorting Nexins ,Glycoproteins ,Mice, Inbred C3H ,Behavior, Animal ,Intracellular Signaling Peptides and Proteins ,Novelty ,Environment, Controlled ,Anxiety Disorders ,Behavior, Addictive ,Mice, Inbred C57BL ,Disease Models, Animal ,Neurology ,Mice, Inbred DBA ,Impulsive Behavior ,Exploratory Behavior ,medicine.symptom ,Psychology ,Neuroscience - Abstract
Both impulsivity in operant tasks and locomotor activity in a novel open field are known to predict the development of addiction-related behavior in rodents. In this study, we investigated to what extent impulsivity in the five-choice serial reaction time task and various measures of novelty exploration are controlled by shared genetic and environmental factors in 12 different inbred mouse strains. No genetic correlation was observed between the level of impulsivity and levels of activity, a low correlation was observed with traditional measures of anxiety-like behavior (impulsive strains tend to be less anxious) and a highly significant correlation was found between impulsivity and specific aspects of movement. Furthermore, we found that impulsivity and all measures of novelty exploration were under control of different environmental factors. Interestingly, in the dorsal medial prefrontal cortex, a brain region involved in impulsivity and activity in novelty exploration tests; these behavioral measures correlated with the expression of different genes (respectively, Frzb, Snx5, BC056474 and the previously identified Glo1). Taken together, our study shows that impulsivity and activity in novelty exploration tests are genetically and environmentally distinct, suggesting that mouse models of these behaviors provide complementary insights into the development of substance abuse disorder. © 2009 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society.
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- 2009
8. A 1-night operant learning task without food-restriction differentiates among mouse strains in an automated home-cage environment
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Remmelink, E., Loos, M., Koopmans, B., Aarts, E., van der Sluis, S., Smit, A.B., Verhage, M., Brussaard, A.B., Borst, J.G., Elgersma, Y, Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Spruijt, B.M., de Zeeuw, C.I., Netherlands Institute for Neuroscience (NIN), Center for Neurogenomics and Cognitive Research, Functional Genomics, Complex Trait Genetics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, General Practice, Erasmus MC other, Human genetics, NCA - Brain mechanisms in health and disease, and Cognitive and Systems Neuroscience (SILS, FNWI)
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Male ,Elementary cognitive task ,Process (engineering) ,education ,Motor Activity ,Inbred C57BL ,Laboratory ,Task (project management) ,Developmental psychology ,Automation ,Operant ,Mice ,Behavioral Neuroscience ,Inbred DBA ,Animals ,Operant conditioning ,Protocol (object-oriented programming) ,Inbred BALB C ,Automation, Laboratory ,Mice, Inbred BALB C ,Animal ,Repertoire ,Cognition ,Housing, Animal ,Mice, Inbred C57BL ,Learning curve ,Food ,Mice, Inbred DBA ,Housing ,Exploratory Behavior ,Conditioning, Operant ,Psychology ,Learning Curve ,Conditioning ,Cognitive psychology - Abstract
Individuals are able to change their behavior based on its consequences, a process involving instrumental learning. Studying instrumental learning in mice can provide new insights in this elementary aspect of cognition. Conventional appetitive operant learning tasks that facilitate the study of this form of learning in mice, as well as more complex operant paradigms, require labor-intensive handling and food deprivation to motivate the animals. Here, we describe a 1-night operant learning protocol that exploits the advantages of automated home-cage testing and circumvents the interfering effects of food restriction. The task builds on behavior that is part of the spontaneous exploratory tepertoire during the days before the task. We compared the behavior of C57BL/6J, BALB/cJ and DBA/2J mice and found various differences in behavior during this task, but no differences in learning curves. BALB/cJ mice showed the largest instrumental learning response, providing a superior dynamic range and statistical power to study instrumental learning by using this protocol. Insights gained with this home-cage-based learning protocol without food restriction will be valuable for the development of other, more complex, cognitive tasks in automated home-cages. (C) 2015 Elsevier B.V. All rights reserved.
- Published
- 2015
9. Sheltering behavior and locomotor activity in 11 genetically diverse common inbred mouse strains using home-cage monitoring
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Loos, M., Koopmans, B., Aarts, E., Maroteaux, G., van der Sluis, S., Verhage, M., Smit, A.B., Brussaard, A.B., Borst, J.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Spruijt, Berry, de Zeeuw, C.I., Sub Animal Ecology, Bedrijfsvoering, Animal Ecology, Erasmus MC other, Cognitive and Systems Neuroscience (SILS, FNWI), Center for Neurogenomics and Cognitive Research, Functional Genomics, Molecular and Cellular Neurobiology, AIMMS, Complex Trait Genetics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Netherlands Institute for Neuroscience (NIN), Human genetics, and NCA - Brain mechanisms in health and disease
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Activity Cycles ,Heredity ,Mice, Inbred A ,Inbred Strains ,lcsh:Medicine ,Motor Activity ,Biology ,Research and Analysis Methods ,Locomotor activity ,Mice ,Behavioral Neuroscience ,Model Organisms ,Species Specificity ,Inbred strain ,Mice, Inbred NOD ,Computational Techniques ,Genetics ,Animals ,Habituation ,lcsh:Science ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Multidisciplinary ,Behavior, Animal ,Quantitative Traits ,Strain (biology) ,lcsh:R ,Biology and Life Sciences ,SDG 10 - Reduced Inequalities ,Mice, Inbred C57BL ,Phenotypes ,Behavioral test ,Mice, Inbred DBA ,Principal component analysis ,Home cage ,lcsh:Q ,High dimensionality ,Research Article ,Neuroscience - Abstract
Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ). Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive home-cage assessment may greatly aid gene function analyses and drug target discovery.
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- 2014
10. 3D-FISH analysis of ribosomal RNA genes organization during early mouse embryonic development
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Maimouna Koné, Marie Cournut, Renaud Fleurot, Martine Chebrout, Galjart, N., Pierre Adenot, Nathalie Beaujean, Amélie Bonnet-Garnier, Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), Department of Cell Biology and Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), and Centre National de la Recherche Scientifique (CNRS). FRA. EpigeneSys network of excellence..
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nucleus ,chromocenter ,embryo ,chromatin ,rdna ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,nucleolus ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,mouse ,epigenetic - Abstract
absent
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- 2013
11. Candidate genes in ocular dominance plasticity
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Rietman, M.L., Sommeijer, J.-P., Levelt, C.N., Heimel, J.A., Brussaard, A.B., Borst, J.G.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Pennartz, C.M., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., and Cognitive and Systems Neuroscience (SILS, FNWI)
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Genetics ,Candidate gene ,MAPK8 ,General Neuroscience ,GNAI1 ,Biology ,ocular dominance ,lcsh:RC321-571 ,PPP1R1B ,Hypothesis and Theory ,plasticity ,Gene expression ,Cholecystokinin B receptor ,Recombinant inbred ,Gene ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Function (biology) ,Neuroscience ,Visual Cortex - Abstract
The objective of this study was to identify new candidate genes involved in experience-dependent plasticity. To this aim, we combined previously obtained data from recombinant inbred BXD strains on ocular dominance (OD) plasticity and gene expression levels in the neocortex. We validated our approach using a list of genes which alter OD plasticity when inactivated. The expression levels of one fifth of these genes correlated with the amount of OD plasticity. Moreover, the two genes with the highest relative inter-strain differences were among the correlated genes. This suggests that correlation between gene expression levels and OD plasticity is indeed likely to point to genes with a causal role in modulating or generating plasticity in the visual cortex. After this validation on known plasticity genes, we identified new candidate genes by a multi-step approach. First, a list was compiled of all genes of which the expression level in BXD strains correlate with the amount of OD plasticity. To narrow this list to the more promising candidates, we took its cross-section with a list of genes co-regulated with the sensitive period for OD plasticity and a list of genes associated with pathways implicated in OD plasticity. This analysis resulted in a list of 32 candidate genes. The list contained unproven, but not surprising, candidates, such as the genes for IGF-1, NCAM1, NOGO-A, the gamma2 subunit of the GABA(A) receptor, acetylcholine esterase and the catalytic subunit of cAMP-dependent protein kinase A. This was indicative of the viability of our approach, but more interesting were the novel candidate genes: Akap7, Akt1, Camk2d, Cckbr, Cd44, Crim1, Ctdsp2, Dnajc5, Gnai1, Itpka, Mapk8, Nbea, Nfatc3, Nlk, Npy5r, Phf21a, Phip, Ppm1l, Ppp1r1b, Rbbp4, Slc1a3, Slit2, Socs2, Spock3, St8sia1, Zfp207. The possible role of some of these candidates is discussed in the article.
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- 2012
12. High-throughput phenotyping of avoidance learning in mice discriminates different genotypes and identifies a novel gene
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Maroteaux, G., Loos, M., van der Sluis, S., Koopmans, B., Aarts, E., Gassen, K., Geurts, A., Brussaard, A.B., Borst, J.G.G., Elgersma, Y., Galjart, N., van der Horst, G.T.J., Levelt, C.N., Pennartz, C.M.A., de Zeeuw, C.I., Largaespada, D.A., Spruijt, B.M., Stiedl, O., Smit, A.B., Verhage, M., and Cognitive and Systems Neuroscience (SILS, FNWI)
- Abstract
Recognizing and avoiding aversive situations are central aspects of mammalian cognition. These abilities are essential for health and survival and are expected to have a prominent genetic basis. We modeled these abilities in eight common mouse inbred strains covering ∼75% of the species' natural variation and in gene-trap mice (>2000 mice), using an unsupervised, automated assay with an instrumented home cage (PhenoTyper) containing a shelter with two entrances. Mice visited this shelter for 20-1200 times/24 h and 71% of all mice developed a significant and often strong preference for one entrance. Subsequently, a mild aversive stimulus (shelter illumination) was automatically delivered when mice used their preferred entrance. Different genotypes developed different coping strategies. Firstly, the number of entries via the preferred entrance decreased in DBA/2J, C57BL/6J and 129S1/SvImJ, indicating that these genotypes associated one specific entrance with the aversive stimulus. Secondly, mice started sleeping outside (C57BL/6J, DBA/2J), indicating they associated the shelter, in general, with the aversive stimulus. Some mice showed no evidence for an association between the entrance and the aversive light, but did show markedly shorter shelter residence times in response to illumination, indicating they did perceive illumination as aversive. Finally, using this assay, we screened 43 different mutants, which yielded a novel gene, specc1/cytospinB. This mutant showed profound and specific delay in avoidance learning. Together, these data suggest that different genotypes express distinct learning and/or memory of associations between shelter entrance and aversive stimuli, and that specc1/cytospinB is involved in this aspect of cognition.
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- 2012
13. A novel QTL underlying early-onset, low-frequency hearing loss in BXD recombinant inbred strains
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Nagtegaal, A.P., Spijker, S., Crins, T.T.H., Brussaard, A.B., Borst, J.G.G., Elgersma, Y., Galjart, N., van der Horst, G.T.J., Levelt, C.N., Pennartz, C.M., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., and Cognitive and Systems Neuroscience (SILS, FNWI)
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otorhinolaryngologic diseases - Abstract
The DBA/2J inbred strain of mice has been used extensively in hearing research as it suffers from early-onset, progressive hearing loss. Initially, it mostly affects high frequencies, but already at 2-3 months hearing loss becomes broad. In search for hearing loss genes other than Cadherin 23 (otocadherin) and fascin-2, which make a large contribution to the high-frequency deficits, we used a large set of the genetic reference population of BXD recombinant inbred strains. For frequencies 4, 8, 16 and 32 kHz, auditory brainstem response hearing thresholds were longitudinally determined from 2-3 up to 12 weeks of age. Apart from a significant, broad quantitative trait locus (QTL) for high-frequency hearing loss on chromosome 11 containing the fascin-2 gene, we found a novel, small QTL for low-frequency hearing loss on chromosome 18, from hereon called ahl9. Real-time quantitative polymerase chain reaction of organs of Corti, isolated from a subset of strains, showed that a limited number of genes at the QTL were expressed in the organ of Corti. Of those genes, several showed significant expression differences based on the parental line contributing to the allele. Our results may aid in the future identification of genes involved in low-frequency, early-onset hearing loss.
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- 2012
14. Independent genetic loci for sensorimotor gating and attentional performance in BXD recombinant inbred strains
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Loos, M., Staal, J., Pattij, T., Brussaard, A.B., Borst, J.G., Elgersma, J.W., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M.A., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., Spijker, S., Molecular and Cellular Neurobiology, Functional Genomics, Neuroscience Campus Amsterdam - Systems Biology of the Synapse, AIMMS, Neuroscience Campus Amsterdam - Attention & Cognition, Anatomy and neurosciences, Human genetics, NCA - Systems Biology of the Synapse, NCA - Attention & Cognition, Cognitive and Systems Neuroscience (SILS, FNWI), and Netherlands Institute for Neuroscience (NIN)
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Serial reaction time ,Reflex, Startle ,Startle response ,Genotype ,Decision Making ,Quantitative Trait Loci ,Mice, Inbred Strains ,Gating ,Quantitative trait locus ,Stimulus (physiology) ,Mice ,Behavioral Neuroscience ,Species Specificity ,Inbred strain ,Reflex ,Moro reflex ,Reaction Time ,Genetics ,medicine ,Animals ,Attention ,Prepulse inhibition ,Behavior, Animal ,medicine.diagnostic_test ,Sensory Gating ,Acoustic Stimulation ,Neurology ,Genetic Loci ,Psychology ,Neuroscience ,Cognitive psychology - Abstract
A startle reflex in response to an intense acoustic stimulus is inhibited when a barely detectable pulse precedes the startle stimulus by 30-500 ms. It has been theorized that this phenomenon, named prepulse inhibition (PPI) of a startle response, is an automatic early-stage gating process contributing to the ability to focus attention. Deficits in PPI may therefore contribute to deficits in attentional processing. Both deficits are observed in schizophrenia spectrum disorders. Here, we investigated whether there is overlap in genetic control of PPI and attentional processing phenotypes in the panel of BXD recombinant inbred strains of mice. Using an individually titrated prepulse intensity to handle differences in perceived prepulse intensities among strains, we identified a significant quantitative trait locus (QTL) for PPI at the mid-distal end of chromosome 17. A measure of attentional processing in the five-choice serial reaction time task, response variability, mapped to a different locus on proximal-mid chromosome 16. In addition, the estimated genetic and environmental correlations between PPI and several attentional phenotypes were low and not significant. Taken together, the observation of separate genetic loci for PPI and attention and the absence of genetic and environmental correlations indicate that differences in sensorimotor gating do not contribute to differences in attentional performance. Therefore, it is worth pursuing the causative genes residing in both attention and PPI QTL, as these may contribute to separate molecular pathways implicated in neuropsychiatric diseases, such as schizophrenia. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.
- Published
- 2012
15. Towards mouse models of perseveration: A heritable component in extinction of operant behavior in fourteen standard and recombinant inbred mouse lines
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Malkki, H.A.I., Donga, L.A.B., de Groot, S.E., Brussaard, A.B., Borst, J.G.G., Elgersma, J.W., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M.A., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., Battaglia, F.P., Netherlands Institute for Neuroscience (NIN), Cognitive and Systems Neuroscience (SILS, FNWI), Human genetics, NCA - Systems Biology of the Synapse, Functional Genomics, Molecular and Cellular Neurobiology, Neuroscience Campus Amsterdam - Systems Biology of the Synapse, and AIMMS
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Obsessive-Compulsive Disorder ,Reinforcement Schedule ,Cognitive Neuroscience ,media_common.quotation_subject ,Perseveration ,Experimental and Cognitive Psychology ,Mice, Inbred Strains ,Extinction, Psychological ,Behavioral Neuroscience ,Mice ,Inbred strain ,medicine ,Animals ,Operant conditioning ,media_common ,Adaptive behavior ,Behavior, Animal ,Addiction ,Cognitive flexibility ,social sciences ,Extinction (psychology) ,musculoskeletal system ,humanities ,Disease Models, Animal ,Compulsive Behavior ,Conditioning ,Conditioning, Operant ,medicine.symptom ,Obsessive Behavior ,Psychology ,Neuroscience ,geographic locations - Abstract
Extinction of instrumental responses is an essential skill for adaptive behavior such as foraging. So far, only few studies have focused on extinction following appetitive conditioning in mice. We studied extinction of appetitive operant lever-press behavior in six standard inbred mouse strains (A/J, C3H/HeJ, C57BL/6J, DBA/2J, BALB/cByJ and NOD/Ltj) and eight recombinant inbred mouse lines. From the response rates at the end of operant and extinction training we computed an extinction index, with higher values indicating better capability to omit behavioral responding in absence of reward. This index varied highly across the mouse lines tested, and the variability was partially due to a significant heritable component of 12.6%. To further characterize the relationship between operant learning and extinction, we calculated the slope of the time course of extinction across sessions. While many strains showed a considerable capacity to omit responding when lever pressing was no longer rewarded, we found a few lines showing an abnormally high perseveration in lever press behavior, showing no decay in response scores over extinction sessions. No correlation was found between operant and extinction response scores, suggesting that appetitive operant learning and extinction learning are dissociable, a finding in line with previous studies indicating that these forms of learning are dependent on different brain areas. These data shed light on the heritable basis of extinction learning and may help develop animal models of addictive habits and other perseverative disorders, such as compulsive food seeking and eating.
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- 2011
16. Appetitive operant conditioning in mice: heritability and dissociability of training stages
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Malkki, H.A.I., Donga, L.A.B., de Groot, S.E., Battaglia, F.P., Brussaard, A.B., Borst, J.G.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M.A., Smit, A.B., Spruijt, B.M., Verhage, M., de Zeeuw, C.I., and Cognitive and Systems Neuroscience (SILS, FNWI)
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QTL mapping ,BxD ,business.product_category ,instrumental conditioning ,Cognitive Neuroscience ,behavioral screening ,Nose poke ,complex trait analysis ,lcsh:RC321-571 ,Behavioral Neuroscience ,Operant conditioning ,Food pellet ,Likelihood ratio statistic ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,recombinant-inbred mice ,Original Research ,Lever ,appetitive conditioning ,behavioural screening ,Advanced stage ,Heritability ,Neuropsychology and Physiological Psychology ,Training phase ,Psychology ,business ,Neuroscience - Abstract
To study the heritability of different training stages of appetitive operant conditioning, we carried out behavioural screening of 5 standard inbred mouse strains, 28 recombinant-inbred (BxD) mouse lines and their progenitor strains C57BL/6J and DBA/2J. We also computed correlations between successive training stages to study whether learning deficits at an advanced stage of operant conditioning may be dissociated from normal performance in preceding phases of training.The training consisted of two phases: an operant nose poking phase, in which mice learned to collect a sucrose pellet from a food magazine by nose poking, and an operant lever press and nose poking phase, in which mice had to execute a sequence of these two actions to collect a food pellet. As a measure of magazine oriented exploration, we also studied the nose poke entries in the food magazine during the intertrial intervals at the beginning of the first session of the nose-poke training phase.We found significantly heritable components in initial magazine checking behaviour, operant nose-poking and lever press-nose poking. Performance levels in these phases were positively correlated, but several individual strains were identified that showed poor lever press-nose poking while performing well in preceding training stages. Quantitative trait loci mapping revealed suggestive likelihood ratio statistic peaks for initial magazine checking behaviour and lever press – nose poking. These findings indicate that consecutive stages towards more complex operant behavior show significant heritable components, as well as dissociability between stages in specific mouse strains. These heritable components may reside in different chromosomal areas.
- Published
- 2010
17. Sheltering behavior and locomotor activity in 11 genetically diverse common inbred mouse strains using home-cage monitoring
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Sub Animal Ecology, Bedrijfsvoering, Animal Ecology, Loos, M., Koopmans, B., Aarts, E., Maroteaux, G., van der Sluis, S., Verhage, M., Smit, A.B., Brussaard, A.B., Borst, J.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Spruijt, Berry, de Zeeuw, C.I., Sub Animal Ecology, Bedrijfsvoering, Animal Ecology, Loos, M., Koopmans, B., Aarts, E., Maroteaux, G., van der Sluis, S., Verhage, M., Smit, A.B., Brussaard, A.B., Borst, J.G., Elgersma, Y., Galjart, N., van der Horst, G.T., Levelt, C.N., Pennartz, C.M., Spruijt, Berry, and de Zeeuw, C.I.
- Published
- 2014
18. Motor-Independent Targeting of CLASPs to Kinetochores by CENP-E Promotes Microtubule Turnover and Poleward Flux
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Maffini, S, Maia, ARR, Manning, AL, Maliga, Z, Pereira, AL, Junqueira, M, Shevchenko, A, Hyman, A, Yates, JR, Galjart, N, Compton, DA, Maiato, H, and Instituto de Biologia Molecular e Celular
- Subjects
Flux ,Mitotic Spindle ,Mitosis ,Kinetochores ,Microtubule Turnover - Abstract
Efficient chromosome segregation during mitosis relies on the coordinated activity of molecular motors with proteins that regulate kinetochore attachments to dynamic spindle microtubules [1]. CLASPs are conserved kinetochore- and microtubule-associated proteins encoded by two paralogue genes, clasp1 and clasp2, and have been previously implicated in the regulation of kinetochore-microtubule dynamics [2-4]. However, it remains unknown how CLASPs work in concert with other proteins to form a functional kinetochore-microtubule interface. Here we have identified mitotic interactors of human CLASP1 using a proteomic approach. Among these, the microtubule plus-end directed motor CENP-E [5] was found to form a complex with CLASP1 that co-localizes to multiple structures of the mitotic apparatus in human cells. We found that CENP-E recruits both CLASP1 and CLASP2 to kinetochores independent of its motor activity or the presence of microtubules. Depletion of CLASPs or CENP-E by RNAi in human cells causes a significant and comparable reduction of kinetochore-microtubule poleward flux and turnover rates, as well as rescues spindle bipolarity in Kif2a-depleted cells. We conclude that CENP-E integrates two critical functions that are important for accurate chromosome movement and spindle architecture: one relying directly on its motor activity and the other involving the targeting of key microtubule regulators to kinetochores.
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- 2009
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19. Asymmetric CLASP-dependent nucleation of noncentrosomal microtubules at the trans-Golgi network
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Efimov, A, Kharitonov, A, Efimova, N, Loncarek, J, Miller, PM, Andreyeva, N, Gleeson, P, Galjart, N, Maia, ARR, McLeod, IX, Yates, JR, Khodjakov, A, Maiato, H, Akhmanova, A, Kaverina, I, and Instituto de Biologia Molecular e Celular
- Abstract
Proper organization of microtubule arrays is essential for intracellular trafficking and cell motility. It is generally assumed that most if not all microtubules in vertebrate somatic cells are formed by the centrosome. Here we demonstrate that a large number of microtubules in untreated human cells originate from the Golgi apparatus in a centrosome-independent manner. Both centrosomal and Golgi-emanating microtubules need γ-tubulin for nucleation. Additionally, formation of microtubules at the Golgi requires CLASPs, microtubule-binding proteins that selectively coat non-centrosomal microtubule seeds. We show that CLASPs are recruited to trans-Golgi network (TGN) at the Golgi periphery by the TGN protein GCC185. In sharp contrast to radial centrosomal arrays, microtubules nucleated at the peripheral Golgi compartment are preferentially oriented toward the leading edge in motile cells. We propose that Golgi–emanating microtubules contribute to the asymmetric microtubule networks in polarized cells and support diverse processes including post-Golgi transport to the cell front.
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- 2007
20. Dual Effect of CTCF Loss on Neuroprogenitor Differentiation and Survival
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Watson, L. A., primary, Wang, X., additional, Elbert, A., additional, Kernohan, K. D., additional, Galjart, N., additional, and Berube, N. G., additional
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- 2014
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21. Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency toneurodevelopmental abnormalities in mice : erratum
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Hoogenraad, C.C., Koekkoek, B., Akhmanova, A., Krugers, H., Dortland, B., Miedema, M., van Alphen, A., Kistler, W., Jaegle, M., Koutsourakis, M., van Camp, Nadja, Verhoye, Marleen, Van Der Linden, Anne-Marie, Kaverina, I., Grosveld, F., de Zeeuw, C.I., and Galjart, N.
- Published
- 2002
22. CLIP-170 facilitates the formation of kinetochore-microtubule attachments
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Tanenbaum, M.E., Galjart, N., Vugt, M.A.T.M. van, Medema, R.H., Tanenbaum, M.E., Galjart, N., Vugt, M.A.T.M. van, and Medema, R.H.
- Published
- 2006
23. Differential effects of matrix and growth factors on endothelial and fibroblast motility: application of a modified cell migration assay.
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Horssen, R. van, Galjart, N., Rens, J.A., Eggermont, A.M.M., Hagen, T.L.M. ten, Horssen, R. van, Galjart, N., Rens, J.A., Eggermont, A.M.M., and Hagen, T.L.M. ten
- Abstract
Item does not contain fulltext, Cell migration is crucial in virtually every biological process and strongly depends on the nature of the surrounding matrix. An assay that enables real-time studies on the effects of defined matrix components and growth factors on cell migration is not available. We have set up a novel, quantitative migration assay, which enables unharmed cells to migrate along a defined matrix. Here, we used this so-called barrier-assay to define the contribution of fibronectin (FN) and Collagen-I (Col-I) to vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and lysophosphatidic acid (LPA)-induced cell migration of endothelial cells (EC) and fibroblasts. In EC, both FN and Col-I stimulated migration, but FN-induced motility was random, while net movement was inhibited. Addition of bFGF and VEGF overcame the effect of FN, with VEGF causing directional movement. In contrast, in 3T3 fibroblasts, FN stimulated motility and this effect was enhanced by bFGF. This motility was more efficient and morphologically completely different compared to LPA stimulation. Strikingly, directional migration of EC was not paralleled by higher amounts of stable microtubules (MT) or an increased reorientation of the microtubule-organizing centre (MTOC). For EC, the FN effect appeared concentration dependent; high FN was able to induce migration, while for fibroblasts both low and high concentrations of FN induced motility. Besides showing distinct responses of the different cells to the same factors, these results address contradictive reports on FN and show that the interplay between matrix components and growth factors determines both pattern and regulation of cell migration. J. Cell. Biochem. 99: 1536-1552, 2006. (c) 2006 Wiley-Liss, Inc.
- Published
- 2006
24. Role of CLASP2 in microtubule stabilization and the regulation of persistent motility.
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Drabek, K., Ham, M. van der, Stepanova, T., Draegestein, K., Horssen, R. van, Sayas, C.L., Akhmanova, A., Hagen, T. Ten, Smits, R., Fodde, R., Grosveld, F., Galjart, N., Drabek, K., Ham, M. van der, Stepanova, T., Draegestein, K., Horssen, R. van, Sayas, C.L., Akhmanova, A., Hagen, T. Ten, Smits, R., Fodde, R., Grosveld, F., and Galjart, N.
- Abstract
Contains fulltext : 50157.pdf (publisher's version ) (Closed access), In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT "plus-end-tracking proteins," or +TIPs, have been proposed to regulate selective MT stabilization, including the CLASPs, a complex of CLIP-170, IQGAP1, activated Cdc42 or Rac1, a complex of APC, EB1, and mDia1, and the actin-MT crosslinking factor ACF7. By using mouse embryonic fibroblasts (MEFs) in a wound-healing assay, we show here that CLASP2 is required for the formation of a stable, polarized MT array but that CLIP-170 and an APC-EB1 interaction are not essential. Persistent motility is also hampered in CLASP2-deficient MEFs. We find that ACF7 regulates cortical CLASP localization in HeLa cells, indicating it acts upstream of CLASP2. Fluorescence-based approaches show that GFP-CLASP2 is immobilized in a bimodal manner in regions near cell edges. Our results suggest that the regional immobilization of CLASP2 allows MT stabilization and promotes directionally persistent motility in fibroblasts.
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- 2006
25. The microtubule plus-end-tracking protein CLIP-170 associates with the spermatid manchette and is essential for spermatogenesis
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Akhmanova, A.S., Mausset-Bonnefont, A.-L., Cappellen, W. van, Keijzer, N., Hoogenraad, C.C., Stepanova, T., Drabek, K., Wees, J. van der, Mommaas, M., Onderwater, J., Meulen, H. van der, Tanenbaum, M.E., Medema, R.H., Hoogerbrugge, J., Vreeburg, J., Uringa, E.-J., Grootegoed, J.A., Grosveld, F., Galjart, N., Akhmanova, A.S., Mausset-Bonnefont, A.-L., Cappellen, W. van, Keijzer, N., Hoogenraad, C.C., Stepanova, T., Drabek, K., Wees, J. van der, Mommaas, M., Onderwater, J., Meulen, H. van der, Tanenbaum, M.E., Medema, R.H., Hoogerbrugge, J., Vreeburg, J., Uringa, E.-J., Grootegoed, J.A., Grosveld, F., and Galjart, N.
- Published
- 2005
26. Particle Filtering for Multiple Object Tracking in Dynamic Fluorescence Microscopy Images: Application to Microtubule Growth Analysis
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Smal, I., primary, Draegestein, K., additional, Galjart, N., additional, Niessen, W., additional, and Meijering, E., additional
- Published
- 2008
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27. Erratum: Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice
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Hoogenraad, C C, primary, Koekkoek, B, additional, Akhmanova, A, additional, Krugers, H, additional, Dortland, B, additional, Miedema, M, additional, van Alphen, A, additional, Kistler, W M, additional, Jaegle, M, additional, Koutsourakis, M, additional, Camp, N Van, additional, Verhoye, M, additional, van der Linden, A, additional, Kaverina, I, additional, Grosveld, F, additional, Zeeuw, C I De, additional, and Galjart, N, additional
- Published
- 2002
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28. Characterisation of transcriptionally active and inactive chromatin domains in neurons
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Akhmanova, A., primary, Verkerk, T., additional, Langeveld, A., additional, Grosveld, F., additional, and Galjart, N., additional
- Published
- 2000
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29. Functional analysis of CLIP-115 and its binding to microtubules
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Hoogenraad, C.C., primary, Akhmanova, A., additional, Grosveld, F., additional, De Zeeuw, C.I., additional, and Galjart, N., additional
- Published
- 2000
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30. Cathepsin A Deficiency in Galactosialidosis: Studies of Patients and Carriers in 16 Families
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Kleijer, W J, primary, Geilen, G C, additional, Janse, H C, additional, Van Diggelen, O P, additional, Zhou, Xiao Yan, additional, Galjart, N J, additional, Galjaard, H, additional, and D'azzo, A, additional
- Published
- 1996
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31. Zfp-37Is a Member of the KRAB Zinc Finger Gene Family and Is Expressed in Neurons of the Developing and Adult CNS
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Mazarakis, N., primary, Michalovich, D., additional, Karis, A., additional, Grosveld, F., additional, and Galjart, N., additional
- Published
- 1996
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32. Mouse "protective protein". cDNA cloning, sequence comparison, and expression.
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Galjart, N J, primary, Gillemans, N, additional, Meijer, D, additional, and d'Azzo, A, additional
- Published
- 1990
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33. The centromeric/nucleolar chromatin protein ZFP-37 may function to specify neuronal nuclear domains.
- Author
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Payen, E, Verkerk, T, Michalovich, D, Dreyer, S D, Winterpacht, A, Lee, B, De Zeeuw, C I, Grosveld, F, and Galjart, N
- Abstract
Murine ZFP-37 is a member of the large family of C2H2 type zinc finger proteins. It is characterized by a truncated NH2-terminal Krüppel-associated box and is thought to play a role in transcriptional regulation. During development Zfp-37 mRNA is most abundant in the developing central nervous system, and in the adult mouse expression is restricted largely to testis and brain. Here we show that at the protein level ZFP-37 is detected readily in neurons of the adult central nervous system but hardly in testis. In brain ZFP-37 is associated with nucleoli and appears to contact heterochromatin. Mouse and human ZFP-37 have a basic histone H1-like linker domain, located between KRAB and zinc finger regions, which binds double-stranded DNA. Thus we suggest that ZFP-37 is a structural protein of the neuronal nucleus which plays a role in the maintenance of specialized chromatin domains.
- Published
- 1998
34. Gain adaptation and phase dynamics of compensatory eye movements in mice
- Author
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Koekkoek, S.K.E., Alphen, A.M. v, Burg, J. vd, Grosveld, F., Galjart, N., and Zeeuw, C.I. de
- Abstract
The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate its role in the learning and timing of motor behaviour, eye movements in normal and mutant mice were investigated for the first time with the use of search coils. Wild-type mice showed the ability to increase the gain of their vestibulo-ocular reflex by visuo-vestibular training. This adaptation did not occur in lurcher mice, a natural mouse mutant that completely lacks Purkinje cells. During the optokinetic reflex the phase (timing) of the eye movements of lurchers lagged behind that of wild-type littermates, whereas during the vestibulo-ocular reflex it led that of the wild types. Ablations of different parts of the vestibulocerebellum indicated that the flocculus is necessary for the adaptation and the phase-leading effects of the cerebellum, whereas the nodulus might contribute to its phase-lagging effects. We conclude that Purkinje cells in the vestibulocerebellum are necessary for both learning and timing of compensatory eye movements in mice, and that the flocculus and nodulus may play antagonistic roles in these processes. The present description of the basic principles of cerebellar eye-movement control opens up the possibility to investigate the mechanisms of this motor behaviour at the molecular level in genetically manipulated mutant mice.
- Published
- 1997
35. Lysosomal protective protein/cathepsin A. Role of the "linker" domain in catalytic activation.
- Author
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Bonten, E J, Galjart, N J, Willemsen, R, Usmany, M, Vlak, J M, and d'Azzo, A
- Abstract
Lysosomal protective protein/cathepsin A is a serine carboxypeptidase that forms a complex with beta-galactosidase and neuraminidase. The enzyme is synthesized as a 54-kDa precursor/zymogen and processed into a catalytically active 32- and 20-kDa two-chain form. We have expressed in baculovirus-infected insect cells the human one-chain precursor as well as the two separate subunits in order to establish the mode of catalytic activation of the zymogen and the assembly and activation of the two subunits. Infected insect cells synthesize large quantities of the exogenous proteins, which are glycosylated and secreted but not processed. Co-expression of the two subunits results in their assembly into a two-chain form of 34- and 20-kDa with negligible enzymatic activity. Limited proteolysis with trypsin of the 54-kDa precursor and the reconstituted 34- and 20-kDa form gives rise to a fully active 32- and 20-kDa product. These results enabled us to map the sites of proteolytic cleavage needed for full activation of the cathepsin A zymogen. They further indicate that the 34- and 20-kDa form is a transient processing intermediate that is converted into a mature and active enzyme by removal of a 2-kDa "linker" peptide from the COOH terminus of the 34-kDa subunit.
- Published
- 1995
36. Identification and in VitroReconstitution of Lysosomal Neuraminidase from Human Placenta
- Author
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van der Horst, G T J, Galjart, N J, d'Azzo, A, Galjaard, H, and Verheijen, F W
- Abstract
Lysosomal neuraminidase from human placenta has been obtained in its active form by association of an inactive neuraminidase polypeptide with β-galactosidase and the protective protein. Using a specific antiserum, we have now identified a 66-kDa protein as the inactive neuraminidase polypeptide. It is specifically recognized on immunoblots only in its nonreduced state, and it coprecipitates with neuraminidase activity. The 66-kDa polypeptide is substantially glycosylated (38-kDa protein core with 7–14 N-linked oligosaccharide chains), a feature characteristic of lysosomal integral membrane proteins. Specific removal of the 66-kDa neuraminidase polypeptide from glycoprotein preparations prevents the generation of neuraminidase activity. Removal of β-galactosidase or destruction of the protective protein also hinders the formation of active neuraminidase. Reconstitution of neuraminidase activity is observed after mixing glycoprotein preparations, depleted in different components of the β-galactosidase-neuraminidase-protective protein complex, indicating that all three components of the complex are required for neuramindase activity. Association of the neuraminidase polypeptide and the protective protein generates unstable neuraminidase activity, whereas association with β-galactosidase is required for stability.
- Published
- 1989
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37. Rao-Blackwellized marginal particle filtering for multiple object tracking in molecular bioimaging
- Author
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Smal, I., Draegestein, K., Galjart, N., Wiro Niessen, Meijering, E., Medical Informatics, Cell biology, and Radiology & Nuclear Medicine
38. Identification and in Vitro Reconstitution of Lysosomal Neuraminidase from Human Placenta
- Author
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van der Horst, G T J, primary, Galjart, N J, additional, d'Azzo, A, additional, Galjaard, H, additional, and Verheijen, F W, additional
- Published
- 1989
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39. The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner
- Author
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Sleutels Frank, Soochit Widia, Bartkuhn Marek, Heath Helen, Dienstbach Sven, Bergmaier Philipp, Franke Vedran, Rosa-Garrido Manuel, van de Nobelen Suzanne, Caesar Lisa, van der Reijden Michael, Bryne Jan, van IJcken Wilfred, Grootegoed J, Delgado M, Lenhard Boris, Renkawitz Rainer, Grosveld Frank, and Galjart Niels
- Subjects
CTCF ,CTCFL ,Gametogenesis ,Genome-wide binding ,Nucleosome ,Genetics ,QH426-470 - Abstract
Abstract Background CTCF is a highly conserved and essential zinc finger protein expressed in virtually all cell types. In conjunction with cohesin, it organizes chromatin into loops, thereby regulating gene expression and epigenetic events. The function of CTCFL or BORIS, the testis-specific paralog of CTCF, is less clear. Results Using immunohistochemistry on testis sections and fluorescence-based microscopy on intact live seminiferous tubules, we show that CTCFL is only transiently present during spermatogenesis, prior to the onset of meiosis, when the protein co-localizes in nuclei with ubiquitously expressed CTCF. CTCFL distribution overlaps completely with that of Stra8, a retinoic acid-inducible protein essential for the propagation of meiosis. We find that absence of CTCFL in mice causes sub-fertility because of a partially penetrant testicular atrophy. CTCFL deficiency affects the expression of a number of testis-specific genes, including Gal3st1 and Prss50. Combined, these data indicate that CTCFL has a unique role in spermatogenesis. Genome-wide RNA expression studies in ES cells expressing a V5- and GFP-tagged form of CTCFL show that genes that are downregulated in CTCFL-deficient testis are upregulated in ES cells. These data indicate that CTCFL is a male germ cell gene regulator. Furthermore, genome-wide DNA-binding analysis shows that CTCFL binds a consensus sequence that is very similar to that of CTCF. However, only ~3,700 out of the ~5,700 CTCFL- and ~31,000 CTCF-binding sites overlap. CTCFL binds promoters with loosely assembled nucleosomes, whereas CTCF favors consensus sites surrounded by phased nucleosomes. Finally, an ES cell-based rescue assay shows that CTCFL is functionally different from CTCF. Conclusions Our data suggest that nucleosome composition specifies the genome-wide binding of CTCFL and CTCF. We propose that the transient expression of CTCFL in spermatogonia and preleptotene spermatocytes serves to occupy a subset of promoters and maintain the expression of male germ cell genes.
- Published
- 2012
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40. CTCF regulates the local epigenetic state of ribosomal DNA repeats
- Author
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van de Nobelen Suzanne, Rosa-Garrido Manuel, Leers Joerg, Heath Helen, Soochit Widia, Joosen Linda, Jonkers Iris, Demmers Jeroen, van der Reijden Michael, Torrano Verónica, Grosveld Frank, Delgado M Dolores, Renkawitz Rainer, Galjart Niels, and Sleutels Frank
- Subjects
Genetics ,QH426-470 - Abstract
Abstract Background CCCTC binding factor (CTCF) is a highly conserved zinc finger protein, which is involved in chromatin organization, local histone modifications, and RNA polymerase II-mediated gene transcription. CTCF may act by binding tightly to DNA and recruiting other proteins to mediate its various functions in the nucleus. To further explore the role of this essential factor, we used a mass spectrometry-based approach to screen for novel CTCF-interacting partners. Results Using biotinylated CTCF as bait, we identified upstream binding factor (UBF) and multiple other components of the RNA polymerase I complex as potential CTCF-interacting partners. Interestingly, CTCFL, the testis-specific paralog of CTCF, also binds UBF. The interaction between CTCF(L) and UBF is direct, and requires the zinc finger domain of CTCF(L) and the high mobility group (HMG)-box 1 and dimerization domain of UBF. Because UBF is involved in RNA polymerase I-mediated ribosomal (r)RNA transcription, we analyzed CTCF binding to the rDNA repeat. We found that CTCF bound to a site upstream of the rDNA spacer promoter and preferred non-methylated over methylated rDNA. DNA binding by CTCF in turn stimulated binding of UBF. Absence of CTCF in cultured cells resulted in decreased association of UBF with rDNA and in nucleolar fusion. Furthermore, lack of CTCF led to reduced binding of RNA polymerase I and variant histone H2A.Z near the rDNA spacer promoter, a loss of specific histone modifications, and diminished transcription of non-coding RNA from the spacer promoter. Conclusions UBF is the first common interaction partner of CTCF and CTCFL, suggesting a role for these proteins in chromatin organization of the rDNA repeats. We propose that CTCF affects RNA polymerase I-mediated events globally by controlling nucleolar number, and locally by regulating chromatin at the rDNA spacer promoter, similar to RNA polymerase II promoters. CTCF may load UBF onto rDNA, thereby forming part of a network that maintains rDNA genes poised for transcription.
- Published
- 2010
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41. Axotomy induced reversed microtubules polarity leads to the formation of a vesicles trap and the extension of a growth cone's lamellipodium.
- Author
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Erez, H., Shapira, E., Hoogenraad, C. C., de Zeeuw, C. I., Galjart, N., and Spira, M. E.
- Published
- 2002
42. Expression of cDNA encoding the human “protective protein≓ associated with lysosomal β-galactosidase and neuraminidase: Homology to yeast proteases
- Author
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GALJART, N
- Published
- 1988
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43. Dynamics and structural features of the microtubule plus-ends in interphase mouse fibroblasts
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Zovko, S., Abrahams, J.P., Galjart, N., Mommaas, M.A., and Leiden University
- Subjects
Mouse ,Microtubule ,Fibroblasts - Abstract
Microtubuli (MT) zijn holle buisjes opgebouwd uit eiwit tubuline. Ze zijn meest bekend van hun rol in de celdeling, waarbij ze het genetisch materiaal verdelen over de twee dochtercellen. In een niet delende cell vormen deze buisjes een netwerk door de cel heen en zijn betrokken bij verschillende processen, o.a. transport, cel polarisatie en celmigratie. Microtubuli groeien en krimpen aan hun uiteindes. Het meest dynamische uiteinde wordt ook het plus__eind genoemd. In dit onderzoek hebben we gekeken hoe deze plus__eindjes eruit zien als ze krimpen/ groeien. Zo hebben we mbv een electronen microscoop ingezoemd op de plus__eindjes van de microtubuli en deze in detail beschreven. We vonden negen verschillende vormen die plus__eindjes kunnen aannemen. Met behulp van een truuk hebben we uitgezocht welke vorm van de plus__eindjes behoort bij de krimpende of de groeiende en hoe de transitie van de groei naar de krimp verloopt. Onze resultaten hebben ook uitgewezen dat bepaalde plus__eindjes door de factoren in de cel vastgehouden kunnen worden. Dit betekent dat de structuur van de plus__eind belangrijk zou kunnen zijn voor de interacties met verschillende organellen. Kennis over deze interacties is van belang bij de begrijpen van de processen als celdeling, waarbij de plus__eindjes interactie met het genetisch materiaal aangaan.
- Published
- 2010
44. Renin-angiotensin blockade ameliorates the progression of glomerular injury in podocyte-specific Ctcf knockout mice.
- Author
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Fujioka K, Nagai T, Hattori T, Kagami S, Yasutomo K, Galjart N, Hirayama T, Kawachi H, and Urushihara M
- Abstract
Aim: Several studies have shown that the progression of proteinuria and renal tissue injury is associated with activation of the intrarenal renin-angiotensin system (RAS). CCCTC-binding factor (CTCF) is a DNA-binding factor that plays an essential role in the regulation of gene expression. In the present study, we aimed to investigate the phenotypic effects of CTCF deficiency in podocytes., Methods: Angiotensin II type 1 receptor blockers (ARBs) were administered to the podocyte-specific Ctcf knockout mice, and histological and biochemical analyzes were performed. We also investigated the changes in the expression of podocin in podocyte cell cultures with or without stimulation with angiotensin II from glomeruli isolated using magnetic beads from podocyte-specific Ctcf knockout mice., Results: Mice in which Ctcf was deleted from podocytes developed glomerulopathy and mice developed severe progressive proteinuria, and impaired renal function. Moreover, ARBs suppressed the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Both real-time polymerase chain reaction and western blotting showed that podocin expression was decreased in cell cultures stimulated with angiotensin II. Furthermore, RAS components gene expressions in podocyte cell cultures isolated from podocyte-specific Ctcf knockout mice were significantly increased., Conclusion: These results suggest that RAS is involved in the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Elucidation of the pathophysiology of podocyte-specific Ctcf knockout mice may provide new insights into the relationship between podocyte injury and chronic glomerulonephritis., (© 2024 Asian Pacific Society of Nephrology.)
- Published
- 2024
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45. Chromatin architectural factor CTCF is essential for progesterone-dependent uterine maturation.
- Author
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Hewitt SC, Gruzdev A, Willson CJ, Wu SP, Lydon JP, Galjart N, and DeMayo FJ
- Subjects
- Humans, Female, Animals, Mice, Progesterone, Uterus, Endometrium, Chromatin, Endometrial Neoplasms
- Abstract
Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcf
d/d uterine tissue exhibited a marked reduction in the number of uterine glands compared to those without Ctcf deletion (Ctcff/f mice). Post-pubertal Ctcfd/d uteri were hypoplastic with significant reduction in both the amount of the endometrial stroma and number of glands. Transcriptional profiling revealed increased expression of stem cell molecules Lif, EOMES, and Lgr5, and enhanced inflammation pathways following Ctcf deletion. Analysis of the response of the uterus to steroid hormone stimulation showed that CTCF deletion affects a subset of progesterone-responsive genes. This finding indicates (1) Progesterone-mediated signaling remains functional following Ctcf deletion and (2) certain progesterone-regulated genes are sensitive to Ctcf deletion, suggesting they depend on gene-enhancer interactions that require CTCF. The progesterone-responsive genes altered by CTCF ablation included Ihh, Fst, and Errfi1. CTCF-dependent progesterone-responsive uterine genes enhance critical processes including anti-tumorigenesis, which is relevant to the known effectiveness of progesterone in inhibiting progression of early-stage endometrial tumors. Overall, our findings reveal that uterine Ctcf plays a key role in progesterone-dependent expression of uterine genes underlying optimal post-pubertal uterine development., (© 2023 Federation of American Societies for Experimental Biology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)- Published
- 2023
- Full Text
- View/download PDF
46. Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.
- Author
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Marchal GA, Galjart N, Portero V, and Remme CA
- Subjects
- Humans, Myocardium metabolism, Arrhythmias, Cardiac drug therapy, Arrhythmias, Cardiac metabolism, Microtubules, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Myocytes, Cardiac metabolism
- Abstract
The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies., Competing Interests: Conflict of interest: The authors report no conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2023
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47. Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia.
- Author
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Smits WK, Vermeulen C, Hagelaar R, Kimura S, Vroegindeweij EM, Buijs-Gladdines JGCAM, van de Geer E, Verstegen MJAM, Splinter E, van Reijmersdal SV, Buijs A, Galjart N, van Eyndhoven W, van Min M, Kuiper R, Kemmeren P, Mullighan CG, de Laat W, and Meijerink JPP
- Subjects
- Humans, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Chromatin, Enhancer Elements, Genetic genetics, Mutation, Oncogenes, Repressor Proteins genetics, Repressor Proteins metabolism, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Monoallelic inactivation of CCCTC-binding factor (CTCF) in human cancer drives altered methylated genomic states, altered CTCF occupancy at promoter and enhancer regions, and deregulated global gene expression. In patients with T cell acute lymphoblastic leukemia (T-ALL), we find that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5; 14) (q35; q32.2) rearranged patients, especially when CTCF-binding sites are preserved in between the BCL11B enhancer and the TLX3 oncogene. These solitary intervening sites insulate TLX3 from the enhancer by inducing competitive looping to multiple binding sites near the TLX3 promoter. Reduced CTCF levels or deletion of the intervening CTCF site abrogates enhancer insulation by weakening competitive looping while favoring TLX3 promoter to BCL11B enhancer looping, which elevates oncogene expression levels and leukemia burden., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
48. CTCF loss induces giant lamellar bodies in Purkinje cell dendrites.
- Author
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Hirayama T, Kadooka Y, Tarusawa E, Saitoh S, Nakayama H, Hoshino N, Nakama S, Fukuishi T, Kawanishi Y, Umeshima H, Tomita K, Yoshimura Y, Galjart N, Hashimoto K, Ohno N, and Yagi T
- Subjects
- Animals, Mice, Lamellar Bodies, Cerebellum, Dendrites, Purkinje Cells, Neurodegenerative Diseases
- Abstract
CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neurons. The cerebellum plays an important role in motor function by regulating PCs, which are the sole output neurons, and defects in PCs cause motor dysfunction. However, the role of CTCF in PCs has not yet been explored. Here we found that the absence of CTCF in mouse PCs led to progressive motor dysfunction and abnormal dendritic morphology in those cells, which included dendritic self-avoidance defects and a proximal shift in the climbing fibre innervation territory on PC dendrites. Furthermore, we found the peculiar lamellar structures known as "giant lamellar bodies" (GLBs), which have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe disease. GLBs are localized to PC dendrites and are assumed to be associated with neurodegeneration. They have been noted, however, only in case reports following autopsy, and reports of their existence have been very limited. Here we show that GLBs were reproducibly formed in PC dendrites of a mouse model in which CTCF was deleted. GLBs were not noted in PC dendrites at infancy but instead developed over time. In conjunction with GLB development in PC dendrites, the endoplasmic reticulum was almost absent around the nuclei, the mitochondria were markedly swollen and their cristae had decreased drastically, and almost all PCs eventually disappeared as severe motor deficits manifested. Our results revealed the important role of CTCF during normal development and in maintaining PCs and provide new insights into the molecular mechanism of GLB formation during neurodegenerative disease., (© 2022. The Author(s).)
- Published
- 2022
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49. Chromatin jets define the properties of cohesin-driven in vivo loop extrusion.
- Author
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Guo Y, Al-Jibury E, Garcia-Millan R, Ntagiantas K, King JWD, Nash AJ, Galjart N, Lenhard B, Rueckert D, Fisher AG, Pruessner G, and Merkenschlager M
- Subjects
- Animals, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Polymers metabolism, Mammals metabolism, Cohesins, Chromatin genetics, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism
- Abstract
Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
50. CLASP2 safeguards hematopoietic stem cell properties during mouse and fish development.
- Author
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Klaus A, Clapes T, Yvernogeau L, Basu S, Weijts B, Maas J, Smal I, Galjart N, and Robin C
- Subjects
- Animals, Mice, Hematopoiesis genetics, Hematopoiesis physiology, Microtubule-Associated Proteins metabolism, Proto-Oncogene Proteins c-kit metabolism, Receptor Protein-Tyrosine Kinases metabolism, Hematopoietic Stem Cells metabolism, Zebrafish
- Abstract
Hematopoietic stem cells (HSCs) express a large variety of cell surface receptors that are associated with acquisition of self-renewal and multipotent properties. Correct expression of these receptors depends on a delicate balance between cell surface trafficking, recycling, and degradation and is controlled by the microtubule network and Golgi apparatus, whose roles have hardly been explored during embryonic/fetal hematopoiesis. Here we show that, in the absence of CLASP2, a microtubule-associated protein, the overall production of HSCs is reduced, and the produced HSCs fail to self-renew and maintain their stemness throughout mouse and zebrafish development. This phenotype can be attributed to decreased cell surface expression of the hematopoietic receptor c-Kit, which originates from increased lysosomal degradation in combination with a reduction in trafficking to the plasma membrane. A dysfunctional Golgi apparatus in CLASP2-deficient HSCs seems to be the underlying cause of the c-Kit expression and signaling imbalance., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
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