Abstract
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.
Highlights
The development of the cortex is a delicate balance between proliferation, differentiation, and migration of neural progenitors (NPs)
A targeting vector was designed with loxp sites flanking exons 2–4, and a neomycin-resistance cassette (PGK-neo) inserted downstream of exon 4 inside the loxP sites (Supplemental Fig. S1A)
To avoid the potential unexpected effects of PGK-neo insertion, the neo cassette was removed by crossing with Actin-Flp transgenic mice
Summary
The development of the cortex is a delicate balance between proliferation, differentiation, and migration of neural progenitors (NPs). The cortex is comprised of both excitatory and inhibitory neurons, which interact within neuronal circuits to mediate cortical functions Though both types of neurons reside in the cortex, they arise from different embryonic brain regions, and from different NPs. Excitatory neurons are generated from NPs residing in the ventricular zone (VZ)/subventricular zone (SVZ) of the lateral ventricle. Excitatory neurons are generated from NPs residing in the ventricular zone (VZ)/subventricular zone (SVZ) of the lateral ventricle These progenitors undergo asymmetric division to concurrently renew themselves, and to generate the immature neurons that will migrate up the radial glia and differentiate into excitatory neurons in the cortex. Inhibitory interneurons arise from the ganglionic eminence (GE), comprised of the lateral, caudal, and medial ganglionic eminence (LGE, CGE, and MGE respectively), and undergo tangential migration to reach the cortex. Neuropeptide Y (NPY) and calretinin (CR) interneurons all originate from a combination of the MGE and CGE1
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