A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors

Abstract

BackgroundNonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear.ResultWe found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment.ConclusionsOur studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-015-0045-7) contains supplementary material, which is available to authorized users.

The exon junction complex in neural development and neurodevelopmental disease

“…Although both studies are concordant regarding outcomes of Rbm8a loss of function, there is some discrepancy in overexpression phenotypes. While our group did not observe overexpression phenotypes in the developing cortex, Zou et al (2015) report reduced cell cycle exit and less neuron production upon overexpression. These differences could be due to the timing of the experiment, nature of overexpression, or brain region in which overexpression was examined.…”

“…Upon completion of neurogenesis, Emx1‐ Cre; Rbm8a lox/+ mice displayed disorganized cortical layers, with preferential loss of upper layer neurons. Some of these results were independently corroborated by another group, who used shRNA knockdown of Rbm8a in neural progenitor culture (Zou et al, 2015). Consistent with our study, the authors find Rbm8a knockdown increases cell cycle exit and neuron production.…”

Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability

“…Therefore, the observation of the HYDIN paralog expressed in humans may be a candidate gene for microcephaly, since it is only expressed in the brain and is important in head size determination [Brunetti-Pierri et al, 2008;Olbrich et al, 2012]. Recently, it was shown that the RBM8A gene within the 1q21.1 region, besides its role in the thrombocytopenia-absent radius syndrome genesis, also disrupts the embryonic cortical development resulting in neurodevelopmental phenotypes associated to microcephaly [Mao et al, 2015;Zou et al, 2015].…”

Copy number variant syndromes are frequent in schizophrenia: progressing towards a CNV-schizophrenia model

“…Perhaps not surprisingly, most of the SCZ-related genes seen within the CNVs identified have also been associated with other neuropsychiatric and neurodevelopmental conditions, contributing further evidence to support the neurodevelopmental continuum model (Davis et al, 2016; Owen and O’Donovan, 2017). For example, the RMB8A gene contained within the 1q21.1 microdeletion in patient 15 has been associated with ID and anxiety behaviours (Alachkar et al, 2013; Gamba et al, 2016; Zou et al, 2015), while deletions of NRXN1 , seen in two patients, are strongly associated with neuropsychiatric and neurodevelopmental disorders, including SCZ and ASD (Kirov et al, 2009; Marshall et al, 2017; Rujescu et al, 2008). Deletion of LMAN2L , a gene associated with increased risk for SCZ, bipolar disorder and ID (Lim et al, 2014; Rafiullah et al, 2016), was found in three patients.…”