Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Molecular Autism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13229-020-00409-3 |
| _version_ | 1828927738437697536 |
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| author | Shaun Hurley Conor Mohan Philipp Suetterlin Robert Ellingford Kimberley L. H. Riegman Jacob Ellegood Angela Caruso Caterina Michetti Olivier Brock Romy Evans Fabrizio Rudari Alessio Delogu Maria Luisa Scattoni Jason P. Lerch Cathy Fernandes M. Albert Basson |
| author_facet | Shaun Hurley Conor Mohan Philipp Suetterlin Robert Ellingford Kimberley L. H. Riegman Jacob Ellegood Angela Caruso Caterina Michetti Olivier Brock Romy Evans Fabrizio Rudari Alessio Delogu Maria Luisa Scattoni Jason P. Lerch Cathy Fernandes M. Albert Basson |
| author_sort | Shaun Hurley |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T23:54:07Z |
| format | Article |
| id | doaj.art-9cd56a17e41646d2b90944d9def5907e |
| institution | Directory Open Access Journal |
| issn | 2040-2392 |
| language | English |
| last_indexed | 2024-12-13T23:54:07Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Autism |
| spelling | doaj.art-9cd56a17e41646d2b90944d9def5907e2022-12-21T23:26:41ZengBMCMolecular Autism2040-23922021-02-0112112110.1186/s13229-020-00409-3Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical developmentShaun Hurley0Conor Mohan1Philipp Suetterlin2Robert Ellingford3Kimberley L. H. Riegman4Jacob Ellegood5Angela Caruso6Caterina Michetti7Olivier Brock8Romy Evans9Fabrizio Rudari10Alessio Delogu11Maria Luisa Scattoni12Jason P. Lerch13Cathy Fernandes14M. Albert Basson15Centre for Craniofacial and Regenerative Biology, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonDepartment of Medical Biophysics, Mouse Imaging Centre, Hospital for Sick Children, University of TorontoDepartment of Cell Biology and Neuroscience, Neurotoxicology and Neuroendocrinology Section, Istituto Superiore Di SanitàDepartment of Cell Biology and Neuroscience, Neurotoxicology and Neuroendocrinology Section, Istituto Superiore Di SanitàDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Cell Biology and Neuroscience, Neurotoxicology and Neuroendocrinology Section, Istituto Superiore Di SanitàDepartment of Medical Biophysics, Mouse Imaging Centre, Hospital for Sick Children, University of TorontoMRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonCentre for Craniofacial and Regenerative Biology, King’s College LondonAbstract 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.https://doi.org/10.1186/s13229-020-00409-3CHD8ChromatinTBR2AutismCortexHypomorph |
| spellingShingle | Shaun Hurley Conor Mohan Philipp Suetterlin Robert Ellingford Kimberley L. H. Riegman Jacob Ellegood Angela Caruso Caterina Michetti Olivier Brock Romy Evans Fabrizio Rudari Alessio Delogu Maria Luisa Scattoni Jason P. Lerch Cathy Fernandes M. Albert Basson Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Molecular Autism CHD8 Chromatin TBR2 Autism Cortex Hypomorph |
| title | Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
| title_full | Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
| title_fullStr | Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
| title_full_unstemmed | Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
| title_short | Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
| title_sort | distinct dosage sensitive requirements for the autism associated factor chd8 during cortical development |
| topic | CHD8 Chromatin TBR2 Autism Cortex Hypomorph |
| url | https://doi.org/10.1186/s13229-020-00409-3 |
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