The neurogenetics of alternative splicing

Abstract

Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation of splicing is implicated in multiple neurological disorders. We describe recent mouse genetic studies of alternative splicing that reveal its critical role in both neuronal development and the function of mature neurons. We discuss the challenges in understanding the extensive genetic programmes controlled by proteins that regulate splicing, both during development and in the adult brain.

An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling

“…Importantly, all of these results were validated in knockout mice or by using in vivo knockdown strategies (Kusek et al 2012;Licatalosi et al 2012;Shibasaki et al 2013;Quesnel-Vallieres et al 2015;Vuong et al 2016). However, mice that are null for a given RNABP often exhibit pleiotropic phenotypes, which can make it difficult to explain a specific biological role through a single target RNA processing event.…”

“…However, numerous other reports have shown the involvement of tissue-specific RNABPs in neuronal developmental processes and diseases. Specifically, Nova2-, Ptbp1/2-, and Srrm4-dependent alternative splicing controls early cortical development, and Stau2 regulates asymmetric cortical neural stem cell divisions, as evidenced by genetic tools and/or in vivo manipulations (Kusek et al 2012;Li et al 2014;Vuong et al 2016;Zhang et al 2016) The Quaking (Qki) proteins are a STAR (signal transduction and activation of RNA) family of K homology (KH) domain-containing RNABPs and are widely expressed across multiple embryonic and adult tissues. A spontaneous mouse mutant, quaking viable (qk v ), exhibits a deletion of the proximal region of the Qk gene on mouse chromosome 17 and has been used to define Qki functions .…”

PTBP1 and PTBP2 Serve Both Specific and Redundant Functions in Neuronal Pre-mRNA Splicing

“…These neural specific splicing events are regulated by families of special pre-mRNA binding proteins including PTBP, RBFOX, NOVA, MBNL, SRRM4, KHDRBS and TDP43 (Raj and Blencowe, 2015; Vuong et al, 2016). Most of these regulator families include multiple paralogs whose functional redundancy and specificity of targeting are poorly understood.…”

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

“…Alternatively spliced transcripts frequently produce protein isoforms with divergent properties, although the biological significance of the vast majority of these events remains unexplored (Wang et al, 2008; Pan et al, 2008; Keleman et al, 2013; Yang et al, 2016). Many mammalian tissues show cell type and stage specific expression of alternatively spliced transcripts that often fit into biologically coherent pathways (Ule et al, 2005; Fu and Ares, 2014; Yang et al, 2014; Raj and Blencowe, 2015; Bebee et al, 2015; Vuong et al, 2016; Traunmüller et al, 2016; Zhang et al, 2016). The coordinated expression of these splicing-regulatory networks is due in large part to the selective activity of specialized RNA binding proteins that mediate the inclusion or exclusion of alternatively spliced exons based on their recruitment to cis acting elements in target transcripts (Chen and Manley, 2009; Fu and Ares, 2014).…”