Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons / Qiong XU in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 65 p. Titre : Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons Type de document : texte imprimé Auteurs : Qiong XU, Auteur ; Yuan-Yuan LIU, Auteur ; Xiaoming WANG, Auteur ; Guo-he TAN, Auteur ; Hui-Ping LI, Auteur ; Samuel W. HULBERT, Auteur ; Chun-Yang LI, Auteur ; Chun-Chun HU, Auteur ; Z.Q. XIONG, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/*genetics/pathology  Cells, Cultured  Cerebral Cortex/cytology/growth & development  DNA-Binding Proteins/*genetics/metabolism  Humans  Mice  Mice, Inbred C57BL  *Neurogenesis  Neurons/cytology/*metabolism/physiology  *Autism spectrum disorder (ASD)  *chd8  *Chromatin remodeling  *Neurite growth  *Neurodevelopment  Animal Care and Use Committee-approved protocols both at Children's Hospital of  Fudan University ethics approval ID: 2015-87 and Duke University. Human  postmortem brain tissues: The use of archived human postmortem brain tissues is  approved by Institute Review Board at Duke University.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency. En ligne : https://dx.doi.org/10.1186/s13229-018-0244-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons [texte imprimé] / Qiong XU, Auteur ; Yuan-Yuan LIU, Auteur ; Xiaoming WANG, Auteur ; Guo-he TAN, Auteur ; Hui-Ping LI, Auteur ; Samuel W. HULBERT, Auteur ; Chun-Yang LI, Auteur ; Chun-Chun HU, Auteur ; Z.Q. XIONG, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 65 p. Mots-clés : Animals  Autistic Disorder/*genetics/pathology  Cells, Cultured  Cerebral Cortex/cytology/growth & development  DNA-Binding Proteins/*genetics/metabolism  Humans  Mice  Mice, Inbred C57BL  *Neurogenesis  Neurons/cytology/*metabolism/physiology  *Autism spectrum disorder (ASD)  *chd8  *Chromatin remodeling  *Neurite growth  *Neurodevelopment  Animal Care and Use Committee-approved protocols both at Children's Hospital of  Fudan University ethics approval ID: 2015-87 and Duke University. Human  postmortem brain tissues: The use of archived human postmortem brain tissues is  approved by Institute Review Board at Duke University.Not applicableThe authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency. En ligne : https://dx.doi.org/10.1186/s13229-018-0244-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination / Samuel W. HULBERT in Autism Research, 13-10 (October 2020)  

Public ISBD [article]  inAutism Research > 13-10 (October 2020) . - p.1685-1697 Titre : A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination Type de document : texte imprimé Auteurs : Samuel W. HULBERT, Auteur ; Xiaoming WANG, Auteur ; Simisola O. GBADEGESIN, Auteur ; Qiong XU, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur Article en page(s) : p.1685-1697 Langues : Anglais (eng) Mots-clés : Asd  Chd8  autism  mouse behavior  mouse models Index. décimale : PER Périodiques Résumé : Mutations in CHD8 are among the most common autism-causing genetic defects identified in human genomics studies. Therefore, many labs have attempted to model this disorder by generating mice with mutations in Chd8. Using a gene trap inserted after Exon 31, we created a novel Chd8 mutant mouse (Chd8(+/E31T) ) and characterized its behavior on several different assays thought to have face validity for the human condition, attempting to model both the core symptoms (repetitive behaviors and social communication impairments) and common comorbidities (motor deficits, anxiety, and intellectual disability). We found that Chd8(+/E31T) mice showed no difference compared to wild-type mice in amount of self-grooming, reproducing the negative finding most other studies have reported. Unlike some of the other published lines, Chd8(+/E31T) mice did not show deficits in the three-chamber test for social novelty preference. A few studies have examined ultrasonic vocalizations in Chd8 mutant mice, but we are the first to report an increase in call length for adult mice. Additionally, we found that in contrast to previous published lines, Chd8(+/E31T) mice displayed no anxiety-like behaviors or learning impairments but showed paradoxically significant improvement in motor function. The inconsistencies in behavioral phenotypes in the Chd8 mutant mice generated by different laboratories poses a challenge for modeling autism spectrum disorder and preclinical studies in mice going forward and warrants further investigation into the molecular consequences of the different mutations in Chd8 and the functional impact on behavior. LAY SUMMARY: Several different mouse models carrying mutations in the Chd8 gene have been created to study the effects of these autism-causing mutations in the laboratory. The current study characterizes a novel Chd8 mutant mouse model as well as summarizes data from previously published Chd8 mutant mice. The inconsistencies between different studies are concerning, but future research into the reasons why these inconsistencies occur may help us understand why patients with various mutations have different degrees of symptom severity. Autism Res 2020, 13: 1685-1697. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431 [article] A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination [texte imprimé] / Samuel W. HULBERT, Auteur ; Xiaoming WANG, Auteur ; Simisola O. GBADEGESIN, Auteur ; Qiong XU, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur . - p.1685-1697. Langues : Anglais (eng) in Autism Research > 13-10 (October 2020) . - p.1685-1697 Mots-clés : Asd  Chd8  autism  mouse behavior  mouse models Index. décimale : PER Périodiques Résumé : Mutations in CHD8 are among the most common autism-causing genetic defects identified in human genomics studies. Therefore, many labs have attempted to model this disorder by generating mice with mutations in Chd8. Using a gene trap inserted after Exon 31, we created a novel Chd8 mutant mouse (Chd8(+/E31T) ) and characterized its behavior on several different assays thought to have face validity for the human condition, attempting to model both the core symptoms (repetitive behaviors and social communication impairments) and common comorbidities (motor deficits, anxiety, and intellectual disability). We found that Chd8(+/E31T) mice showed no difference compared to wild-type mice in amount of self-grooming, reproducing the negative finding most other studies have reported. Unlike some of the other published lines, Chd8(+/E31T) mice did not show deficits in the three-chamber test for social novelty preference. A few studies have examined ultrasonic vocalizations in Chd8 mutant mice, but we are the first to report an increase in call length for adult mice. Additionally, we found that in contrast to previous published lines, Chd8(+/E31T) mice displayed no anxiety-like behaviors or learning impairments but showed paradoxically significant improvement in motor function. The inconsistencies in behavioral phenotypes in the Chd8 mutant mice generated by different laboratories poses a challenge for modeling autism spectrum disorder and preclinical studies in mice going forward and warrants further investigation into the molecular consequences of the different mutations in Chd8 and the functional impact on behavior. LAY SUMMARY: Several different mouse models carrying mutations in the Chd8 gene have been created to study the effects of these autism-causing mutations in the laboratory. The current study characterizes a novel Chd8 mutant mouse model as well as summarizes data from previously published Chd8 mutant mice. The inconsistencies between different studies are concerning, but future research into the reasons why these inconsistencies occur may help us understand why patients with various mutations have different degrees of symptom severity. Autism Res 2020, 13: 1685-1697. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431

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