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Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 11 (2020)
[article]
Titre : Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : Texte imprimé et/ou numérique Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 74 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Brain overgrowth Chd8 Endoplasmic reticulum stress Macrocephaly Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12?months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1?year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12?months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433
in Molecular Autism > 11 (2020) . - 74 p.[article] Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [Texte imprimé et/ou numérique] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 74 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 74 p.
Mots-clés : Autism spectrum disorder Brain overgrowth Chd8 Endoplasmic reticulum stress Macrocephaly Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12?months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1?year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12?months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 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 A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination / Samuel W. HULBERT in Autism Research, 13-10 (October 2020)
[article]
Titre : A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination Type de document : Texte imprimé et/ou numérique 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
in Autism Research > 13-10 (October 2020) . - p.1685-1697[article] A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination [Texte imprimé et/ou numérique] / 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 Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders / Karina GRIESI-OLIVEIRA in Autism Research, 6-5 (October 2013)
[article]
Titre : Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Karina GRIESI-OLIVEIRA, Auteur ; Daniele Yumi SUNAGA, Auteur ; Lucas ALVIZI, Auteur ; Estevão VADASZ, Auteur ; Maria Rita PASSOS-BUENO, Auteur Article en page(s) : p.354-361 Langues : Anglais (eng) Mots-clés : expression studies androgen signaling CHD8 stem cells of human exfoliated deciduous teeth Index. décimale : PER Périodiques Résumé : Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n?=?7) and control samples (n?=?6). Nearly half of the 683 identified DEGs are expressed in the brain (P?=?0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1296 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=218
in Autism Research > 6-5 (October 2013) . - p.354-361[article] Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders [Texte imprimé et/ou numérique] / Karina GRIESI-OLIVEIRA, Auteur ; Daniele Yumi SUNAGA, Auteur ; Lucas ALVIZI, Auteur ; Estevão VADASZ, Auteur ; Maria Rita PASSOS-BUENO, Auteur . - p.354-361.
Langues : Anglais (eng)
in Autism Research > 6-5 (October 2013) . - p.354-361
Mots-clés : expression studies androgen signaling CHD8 stem cells of human exfoliated deciduous teeth Index. décimale : PER Périodiques Résumé : Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n?=?7) and control samples (n?=?6). Nearly half of the 683 identified DEGs are expressed in the brain (P?=?0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1296 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=218