1Curr. Mol. Med. 2013 Jul 13: 887-99
TitleAn EJC factor RBM8a regulates anxiety behaviors.
AbstractNeuroplasticity depends on the precise timing of gene expression, which requires accurate control of mRNA stability and rapid elimination of abnormal mRNA. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that ensures the speedy degradation of mRNAs carrying premature termination codons (PTCs). This mechanism relies on several key Exon Junction Complex (EJC) factors to distinguish PTCs from normal stop codons. NMD degrades not only aberrant transcripts carrying PTCs, but also normal transcripts harboring a normal stop codon [1]. Intriguingly, mutations in an NMD factor, Upf3b, have been found in patients with autism [2, 3]. A binding partner of Upf3b, RBM8A, is located in the 1q21.1 copy-number variation (CNV) associated with mental retardation, autism [4], schizophrenia [5], and microcephaly [6]. However, the functions of EJC factors and their roles in behavioral regulation are still elusive. RBM8A protein is a core component of the EJC that plays an important role in NMD. Recent genetic study indicated that RBM8A gain-of-function significantly associated with intellectual disability [7]. In this study we investigated the effect of RBM8A overexpression on affective behaviors in mice. Lentivirus expressing RBM8A was infused into the hippocampus of adult mice to conduct behavioral studies including social interaction, open field, elevated plus maze, and forced swimming tests. Our results showed that overexpression of RBM8A in the mouse dentate gyrus (DG) leads to increased anxiety-like behavior, abnormal social interaction and decreased immobile time in forced swimming test (FST). To examine the underlying mechanism, we found that overexpressing RBM8A in cultured primary neurons lead to significant higher frequency of miniature excitatory postsynaptic currents (mEPSCs). To explore the underlying mechanism of RBM8A mediated behavioral changes, RNA-immunoprecipitation (RNA-IP) detected that RBM8A binds to CaMK2, GluR1 and Egr1 mRNA, suggesting that RBM8A may target neuronal genes to regulate behaviors. This is the first study that demonstrates the key role of RBM8A on the emotional behaviors in mice. These results reveal new neural mechanisms by which NMD modulates behaviors and potentially provide a better understanding of pathophysiology underlying psychiatric disorders.
SCZ Keywordsschizophrenia
2Neural Dev 2015 -1 10: 18
TitleA critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.
AbstractNonsense 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.
We 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.
Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.
SCZ Keywordsschizophrenia