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Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development
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-haploin...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905672/ https://www.ncbi.nlm.nih.gov/pubmed/33627187 http://dx.doi.org/10.1186/s13229-020-00409-3 |
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author | Hurley, Shaun Mohan, Conor Suetterlin, Philipp Ellingford, Robert Riegman, Kimberley L. H. Ellegood, Jacob Caruso, Angela Michetti, Caterina Brock, Olivier Evans, Romy Rudari, Fabrizio Delogu, Alessio Scattoni, Maria Luisa Lerch, Jason P. Fernandes, Cathy Basson, M. Albert |
author_facet | Hurley, Shaun Mohan, Conor Suetterlin, Philipp Ellingford, Robert Riegman, Kimberley L. H. Ellegood, Jacob Caruso, Angela Michetti, Caterina Brock, Olivier Evans, Romy Rudari, Fabrizio Delogu, Alessio Scattoni, Maria Luisa Lerch, Jason P. Fernandes, Cathy Basson, M. Albert |
author_sort | Hurley, Shaun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7905672 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-79056722021-02-25 Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Hurley, Shaun Mohan, Conor Suetterlin, Philipp Ellingford, Robert Riegman, Kimberley L. H. Ellegood, Jacob Caruso, Angela Michetti, Caterina Brock, Olivier Evans, Romy Rudari, Fabrizio Delogu, Alessio Scattoni, Maria Luisa Lerch, Jason P. Fernandes, Cathy Basson, M. Albert Mol Autism Research 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. BioMed Central 2021-02-24 /pmc/articles/PMC7905672/ /pubmed/33627187 http://dx.doi.org/10.1186/s13229-020-00409-3 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Hurley, Shaun Mohan, Conor Suetterlin, Philipp Ellingford, Robert Riegman, Kimberley L. H. Ellegood, Jacob Caruso, Angela Michetti, Caterina Brock, Olivier Evans, Romy Rudari, Fabrizio Delogu, Alessio Scattoni, Maria Luisa Lerch, Jason P. Fernandes, Cathy Basson, M. Albert Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development |
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 | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905672/ https://www.ncbi.nlm.nih.gov/pubmed/33627187 http://dx.doi.org/10.1186/s13229-020-00409-3 |
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