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

Neural Dev. 2015 Jun 21:10:18. doi: 10.1186/s13064-015-0045-7.

Abstract

Background: Nonsense 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.

Result: 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.

Conclusions: Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology*
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Gene Expression Regulation, Developmental / genetics*
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurogenesis / physiology*
  • RNA, Small Interfering
  • RNA-Binding Proteins / metabolism*
  • Transfection

Substances

  • RBM8A protein, human
  • RBM8A protein, mouse
  • RNA, Small Interfering
  • RNA-Binding Proteins