Full function of exon junction complex factor, Rbm8a, is critical for interneuron development

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.

The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton

“…We next examined the requirement of the presence of each EJC component during neuronal development by conditionally removing each protein from newborn cortical excitatory neurons. For this, we crossed mice carrying floxed alleles for either Eif4a3, Rbm8a or Magoh with Nex -Cre, which drives Cre expression in all newborn glutamatergic neurons of the neocortex around E11.5-12.5 (Goebbels et al, 2006; Mao et al, 2016b; Mao et al, 2015; McMahon et al, 2014; McSweeney et al, 2020). Cre activity was verified by reporter expression of tdTomato in E14.5 Nex -Cre; Eif4a3 lox/+ ; Ai14 lox/+ cortical sections ( Figure S1J ).…”

“…All animal procedures were approved by the Duke Institutional Animal Care and Use Committee (IACUC) and performed in agreement with the ethical guidelines of the Division of Laboratory Animal Resources (DLAR) from Duke University. We used the following previously described mouse lines: Eif4a3 loxP (Mao et al, 2016b), Rbm8a loxP (McSweeney et al, 2020), Magoh loxP (McMahon et al, 2014) and Neurod6 tm1(cre)Kan ( Nex -Cre) (Goebbels et al, 2006). The following mouse strains were obtained from Jackson Laboratories: C57BL/6J ( wild type ), B6.Cg- Gt(ROSA)26Sor tm14(CAG-tdTomato)Hze /J (Ai14), B6.129S2-Trp53 tm1Tyj /J (p53 LoxP ), and C57BL/6J- Tg(Dcx-DsRED)14Qlu/J ( Dcx ::DsRed).…”

Dissecting Molecular Genetic Mechanisms of 1q21.1 CNV in Neuropsychiatric Disorders

“…Other brain dysfunctions, including psychosis, agenesis of the corpus callosum and hypoplasia of the cerebellar vermis, are present in TAR patients [ 28 , 29 , 30 ]. Consistent with human patient studies, knockdown and knockout of Rbm8a in a mouse model revealed the critical role of RBM8A in neural progenitor cell (NPC) proliferation, neuronal migration and interneuron development, and loss of function in RBM8A in NPCs causes microcephaly [ 31 , 32 , 33 ]. Moreover, RBM8A plays a key role in adult neurogenesis and in regulating anxiety-related behavior [ 34 ], further supporting the important role of RBM8A in psychiatric diseases.…”

Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis

“…The role of SMG6 on interneuron progenitors is reminiscent of a recent study showing that exon-junction complex factor RBM8A is critical for interneuron development [ 55 ]. Consistent with the defects of SMG6 deficient interneurons, key transcription factors that control the cell fate of interneuron progenitors were found dysregulated.…”