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Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development
Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defec...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811508/ https://www.ncbi.nlm.nih.gov/pubmed/31680852 http://dx.doi.org/10.3389/fnmol.2019.00243 |
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author | Alvarez-Saavedra, Matías Yan, Keqin De Repentigny, Yves Hashem, Lukas E. Chaudary, Nidhi Sarwar, Shihab Yang, Doo Ioshikhes, Ilya Kothary, Rashmi Hirayama, Teruyoshi Yagi, Takeshi Picketts, David J. |
author_facet | Alvarez-Saavedra, Matías Yan, Keqin De Repentigny, Yves Hashem, Lukas E. Chaudary, Nidhi Sarwar, Shihab Yang, Doo Ioshikhes, Ilya Kothary, Rashmi Hirayama, Teruyoshi Yagi, Takeshi Picketts, David J. |
author_sort | Alvarez-Saavedra, Matías |
collection | PubMed |
description | Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the Smarca1 gene encoding Snf2l, which is one of two ISWI mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related Smarca5 gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific Smarca5 cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development. |
format | Online Article Text |
id | pubmed-6811508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68115082019-11-01 Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development Alvarez-Saavedra, Matías Yan, Keqin De Repentigny, Yves Hashem, Lukas E. Chaudary, Nidhi Sarwar, Shihab Yang, Doo Ioshikhes, Ilya Kothary, Rashmi Hirayama, Teruyoshi Yagi, Takeshi Picketts, David J. Front Mol Neurosci Neuroscience Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the Smarca1 gene encoding Snf2l, which is one of two ISWI mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related Smarca5 gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific Smarca5 cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development. Frontiers Media S.A. 2019-10-17 /pmc/articles/PMC6811508/ /pubmed/31680852 http://dx.doi.org/10.3389/fnmol.2019.00243 Text en Copyright © 2019 Alvarez-Saavedra, Yan, De Repentigny, Hashem, Chaudary, Sarwar, Yang, Ioshikhes, Kothary, Hirayama, Yagi and Picketts. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Alvarez-Saavedra, Matías Yan, Keqin De Repentigny, Yves Hashem, Lukas E. Chaudary, Nidhi Sarwar, Shihab Yang, Doo Ioshikhes, Ilya Kothary, Rashmi Hirayama, Teruyoshi Yagi, Takeshi Picketts, David J. Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title | Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title_full | Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title_fullStr | Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title_full_unstemmed | Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title_short | Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development |
title_sort | snf2h drives chromatin remodeling to prime upper layer cortical neuron development |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811508/ https://www.ncbi.nlm.nih.gov/pubmed/31680852 http://dx.doi.org/10.3389/fnmol.2019.00243 |
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