TY - JOUR
T1 - Full function of exon junction complex factor, Rbm8a, is critical for interneuron development
AU - McSweeney, Colleen
AU - Dong, Fengping
AU - Chen, Miranda
AU - Vitale, Jessica
AU - Xu, Li
AU - Crowley, Nicole
AU - Luscher, Bernhard
AU - Zou, Donghua
AU - Mao, Yingwei
N1 - Funding Information:
We thank Dr. Lin Gan (University of Rochester School of Medicine) for generation of Rbm8a cKO mice, and Michelle Strulson for her assistance confirming the cKO mice. This project was supported by Scientist Development Grant 13SDG14670072 from American Heart Association, Seed fund from the Pennsylvania State University Social Science Research Institute, and the Penn State CTSI Grant (UL Tr000127) from the National Center for Advancing Translational Sciences, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Richard Ordway, Gong Chen, Bernhard Luscher, Timothy Jegla, Aimin Liu, Douglas Cavener, and Albert Istvan for technical support. We thank Genome Core facility at Pennsylvania State University, and Simon Xi and Thomas Lanz at Pfizer for technical support of RNAseq.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - The formation of the nervous system requires a balance between proliferation, differentiation, and migration of neural progenitors (NPs). Mutations in genes regulating development impede neurogenesis and lead to neuropsychiatric diseases, including autism spectrum disorders (ASDs) and schizophrenia (SZ). Recently, mutations in nonsense-mediated mRNA decay genes have been associated with ASDs, intellectual disability (ID), and SZ. Here, we examine the function of a gene in the exon junction complex, Rbm8a, in the cortical development. When Rbm8a is selectively knocked out in neural stem cells, the resulting mice exhibit microcephaly, early postnatal lethality, and altered distribution of excitatory neurons in the neocortex. Moreover, Rbm8a haploinsufficiency in the central nervous system decreases cell proliferation in the ganglionic eminences. Parvalbumin+ and neuropeptide Y+ interneurons in the cortex are significantly reduced, and distribution of interneurons are altered. Consistently, neurons in the cortex of conditional knockout (cKO) mice show a significant decrease in GABA frequency. Transcriptomic analysis revealed differentially expressed genes enriched in telencephalon development and mitosis. To further investigate the role of Rbm8a in interneuron differentiation, conditional KO of Rbm8a in NKX2.1 interneuron progenitor cells reduces progenitor proliferation and alters interneuron distributions. Taken together, these data reveal a critical role of Rbm8a in interneuron development, and establish that perturbation of this gene leads to profound cortical deficits.
AB - The formation of the nervous system requires a balance between proliferation, differentiation, and migration of neural progenitors (NPs). Mutations in genes regulating development impede neurogenesis and lead to neuropsychiatric diseases, including autism spectrum disorders (ASDs) and schizophrenia (SZ). Recently, mutations in nonsense-mediated mRNA decay genes have been associated with ASDs, intellectual disability (ID), and SZ. Here, we examine the function of a gene in the exon junction complex, Rbm8a, in the cortical development. When Rbm8a is selectively knocked out in neural stem cells, the resulting mice exhibit microcephaly, early postnatal lethality, and altered distribution of excitatory neurons in the neocortex. Moreover, Rbm8a haploinsufficiency in the central nervous system decreases cell proliferation in the ganglionic eminences. Parvalbumin+ and neuropeptide Y+ interneurons in the cortex are significantly reduced, and distribution of interneurons are altered. Consistently, neurons in the cortex of conditional knockout (cKO) mice show a significant decrease in GABA frequency. Transcriptomic analysis revealed differentially expressed genes enriched in telencephalon development and mitosis. To further investigate the role of Rbm8a in interneuron differentiation, conditional KO of Rbm8a in NKX2.1 interneuron progenitor cells reduces progenitor proliferation and alters interneuron distributions. Taken together, these data reveal a critical role of Rbm8a in interneuron development, and establish that perturbation of this gene leads to profound cortical deficits.
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U2 - 10.1038/s41398-020-01065-0
DO - 10.1038/s41398-020-01065-0
M3 - Article
C2 - 33154347
AN - SCOPUS:85095132399
SN - 2158-3188
VL - 10
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 379
ER -