Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. Mus musculus

Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not completely understood. To address these questions, we have generated mice lacking the vertebrate- and neural-specific Ser/Arg-repeat related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems, in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to non-neural patterns for different classes of splicing events. The main component of the altered AS program comprises 3-27 nucleotide neural microexons, an emerging class of highly conserved alternative splicing event associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nucleotide nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100, and they further link these functions to a conserved program of neural microexon splicing. Overall design: mRNA profiles of mouse control or nSR100/Srrm4 KO cortex or hippocampus using high-throughput sequencing data.