Alternative Splicing in Neurogenesis and Brain Development

Abstract

Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

Keywords: alternative splicing; neurogenesis; neuronal development; neuronal differentiation; neuronal migration; splicing factors.

Figure 1

Function of splicing regulatory proteins in the mammalian nervous system. Splicing factors (yellow boxes) participate in a number of different processes during brain development, including (A) self-renewing division and fate determination of neural stem cells, and neuronal cell differentiation, (B) migration of newly born neuron during corticogenesis, and (C) synaptogenesis or neural activity-regulated synaptic function.

Figure 2

RBM4 regulates PTBP1 expression or splicing activity by modulating exon selection during the differentiation of non-neuronal or neuronal cells. (A) RBM4 suppresses the cellular level of both PTBP1 and PTBP2 during non-neuronal cell differentiation via activating exon 11/10 skipping of PTBP1/PTBP2 mRNAs (Left). PTBP1 also downregulates PTBP2 level by promoting exon 10 skipping of PTBP2 mRNA (Left). During neuronal differentiation, PTBP1 level is downregulated by miR-124, whereas RBM4-induced exon 9 skipping of PTBP1 mRNA generates an isoform with reduced splicing activity, which compromises the splicing effect of PTBP1 during neural differentiation (Right). (B) Exclusion of exon 11/10 (red box) of PTBP1/PTBP2 generates splicing isoforms with a premature translation-termination codon, and such isoforms are subjected to degradation via alternative splicing-coupled nonsense-mediated decay. RBM4 promotes exon 9 (blue box) skipping, which is specific to PTBP1.