Regulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing

Abstract

Posttranscriptional mechanisms provide powerful means to expand the coding power of genomes. In nervous systems, alternative splicing has emerged as a fundamental mechanism not only for the diversification of protein isoforms but also for the spatiotemporal control of transcripts. Thus, alternative splicing programs play instructive roles in the development of neuronal cell type-specific properties, neuronal growth, self-recognition, synapse specification, and neuronal network function. Here we discuss the most recent genome-wide efforts on mapping RNA codes and RNA-binding proteins for neuronal alternative splicing regulation. We illustrate how alternative splicing shapes key steps of neuronal development, neuronal maturation, and synaptic properties. Finally, we highlight efforts to dissect the spatiotemporal dynamics of alternative splicing and their potential contribution to neuronal plasticity and the mature nervous system.

Chromatin-mediated alternative splicing regulates cocaine reward behavior

“…Alternative splicing is a key mechanism for gene regulation in brain. Neuron-specific isoform expression is essential to proper cell-type specification as shown from recent studies in neuronal development (Furlanis and Scheiffele, 2018;Saito et al, 2019;Schwartzentruber et al, 2018), disease (Gandal et al, 2018;de la Torre-Ubieta et al, 2016;Parikshak et al, 2016;Voineagu et al, 2011) and activity Parikshak et al, 2016;Quesnel-Vallières et al, 2016). While many neurological diseases, including autism (Quesnel-Vallières et al, 2016;Voineagu et al, 2011), Rett syndrome (Cheng et al, 2017;Kriaucionis and Bird, 2004;Li et al, 2016), Huntington's disease (Lin et al, 1993;Sathasivam et al, 2013;Wood, 2013), spinal muscular atrophy (Cartegni et al, 2006;Lorson et al, 1999;Parente and Corti, 2018;Xiong et al, 2015) and schizophrenia (Gandal et al, 2018;Glatt et al, 2011;Morikawa and Manabe, 2010;Nakata et al, 2009;Wu et al, 2012) have been linked to disruptions in alternative splicing, this mechanism of gene regulation is understudied in the context of drug abuse and addiction.…”

Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function

“…It is essential to understand the mechanisms that regulate alternative pre mRNA splicing. This dynamic process regulates exon composition for >95% of multi-exon genes according to cell-type and influenced by development, cellular activity and disease (Furlanis and Scheiffele, 2018). The cell-specific actions of RNA binding proteins are relatively well described; these splicing factors promote or repress spliceosome recruitment to pre mRNAs via cis -elements proximal to intron-exon splice junctions (Vuong et al, 2016).…”

“…Mechanisms that regulate cell-specific alternative splicing of physiologically significant events are determined for a relatively small number of exons (Furlanis and Scheiffele, 2018; Lopez Soto et al, 2019). Voltage-gated ion channel genes, essential for all electrical signaling in the nervous system, are large multi-exon genes subject to extensive alternative splicing.…”

tappAS: a comprehensive computational framework for the analysis of the functional impact of differential splicing

“…While some discrepancy exist on the actual functional role of transcript isoform diversity 16,17 . AltTP has been proven to be implicated in differentiation [18][19][20] , tissue identity 21,22 , development 13,23 , stress response 24 and disease [25][26][27][28] . Beyond these well known effects, several studies have shown enrichment of spliced exons in disordered regions mediating new protein interactions 29 and remodeling of proteinprotein interaction in a tissue-specific manner 30,31 .…”