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Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior / B. L. THOMPSON in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)
[article]
Titre : Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior Type de document : Texte imprimé et/ou numérique Auteurs : B. L. THOMPSON, Auteur ; P. LEVITT, Auteur Article en page(s) : p.35 Langues : Anglais (eng) Mots-clés : Autism Behavior Fear learning Gene dose Met Mouse Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35[article] Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior [Texte imprimé et/ou numérique] / B. L. THOMPSON, Auteur ; P. LEVITT, Auteur . - p.35.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35
Mots-clés : Autism Behavior Fear learning Gene dose Met Mouse Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models / Ugne KLIBAITE in Molecular Autism, 13 (2022)
[article]
Titre : Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models Type de document : Texte imprimé et/ou numérique Auteurs : Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/genetics Disease Models, Animal Female Male Membrane Proteins/genetics Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins/genetics Phenotype Tuberous Sclerosis Complex 1 Protein/genetics Autism Behavior Cerebellum Clustering Mouse Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477
in Molecular Autism > 13 (2022) . - 12 p.[article] Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models [Texte imprimé et/ou numérique] / Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur . - 12 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 12 p.
Mots-clés : Animals Autism Spectrum Disorder/genetics Disease Models, Animal Female Male Membrane Proteins/genetics Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins/genetics Phenotype Tuberous Sclerosis Complex 1 Protein/genetics Autism Behavior Cerebellum Clustering Mouse Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons / Catarina M. SEABRA in Molecular Autism, 11 (2020)
[article]
Titre : Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur Article en page(s) : 45 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 45 p.[article] Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons [Texte imprimé et/ou numérique] / Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur . - 45 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 45 p.
Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development / S. HURLEY in Molecular Autism, 12 (2021)
[article]
Titre : Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Type de document : Texte imprimé et/ou numérique Auteurs : S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 16 p.[article] Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development [Texte imprimé et/ou numérique] / S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur . - 16 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 16 p.
Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 / S. HOSIE in Autism Research, 12-7 (July 2019)
[article]
Titre : Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 Type de document : Texte imprimé et/ou numérique Auteurs : S. HOSIE, Auteur ; M. ELLIS, Auteur ; M. SWAMINATHAN, Auteur ; F. RAMALHOSA, Auteur ; G. O. SEGER, Auteur ; Gayathri K. BALASURIYA, Auteur ; C. GILLBERG, Auteur ; M. RASTAM, Auteur ; L. CHURILOV, Auteur ; S. J. MCKEOWN, Auteur ; N. YALCINKAYA, Auteur ; P. URVIL, Auteur ; Tor SAVIDGE, Auteur ; C. A. BELL, Auteur ; O. BODIN, Auteur ; J. WOOD, Auteur ; A. E. FRANKS, Auteur ; Joel C. BORNSTEIN, Auteur ; E. L. HILL-YARDIN, Auteur Année de publication : 2019 Article en page(s) : p.1043-1056 Langues : Anglais (eng) Mots-clés : autism gastrointestinal symptoms gut motility immunofluorescence mouse neuroligin-3 Index. décimale : PER Périodiques Résumé : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. En ligne : http://dx.doi.org/10.1002/aur.2127 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402
in Autism Research > 12-7 (July 2019) . - p.1043-1056[article] Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 [Texte imprimé et/ou numérique] / S. HOSIE, Auteur ; M. ELLIS, Auteur ; M. SWAMINATHAN, Auteur ; F. RAMALHOSA, Auteur ; G. O. SEGER, Auteur ; Gayathri K. BALASURIYA, Auteur ; C. GILLBERG, Auteur ; M. RASTAM, Auteur ; L. CHURILOV, Auteur ; S. J. MCKEOWN, Auteur ; N. YALCINKAYA, Auteur ; P. URVIL, Auteur ; Tor SAVIDGE, Auteur ; C. A. BELL, Auteur ; O. BODIN, Auteur ; J. WOOD, Auteur ; A. E. FRANKS, Auteur ; Joel C. BORNSTEIN, Auteur ; E. L. HILL-YARDIN, Auteur . - 2019 . - p.1043-1056.
Langues : Anglais (eng)
in Autism Research > 12-7 (July 2019) . - p.1043-1056
Mots-clés : autism gastrointestinal symptoms gut motility immunofluorescence mouse neuroligin-3 Index. décimale : PER Périodiques Résumé : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. En ligne : http://dx.doi.org/10.1002/aur.2127 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development / J. ELLEGOOD in Molecular Autism, 12 (2021)
PermalinkMaintaining Mice for Neurobehavioral Examination / Pierre L. ROUBERTOUX
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