Regulation of Vertebrate Nervous System Alternative Splicing and Development by an SR-Related Protein

Abstract

Alternative splicing is a key process underlying the evolution of increased proteomic and functional complexity and is especially prevalent in the mammalian nervous system. However, the factors and mechanisms governing nervous system-specific alternative splicing are not well understood. Through a genome-wide computational and expression profiling strategy, we have identified a tissue- and vertebrate-restricted Ser/Arg (SR) repeat splicing factor, the neural-specific SR-related protein of 100 kDa (nSR100). We show that nSR100 regulates an extensive network of brain-specific alternative exons enriched in genes that function in neural cell differentiation. nSR100 acts by increasing the levels of the neural/brain-enriched polypyrimidine tract binding protein and by interacting with its target transcripts. Disruption of nSR100 prevents neural cell differentiation in cell culture and in the developing zebrafish. Our results thus reveal a critical neural-specific alternative splicing regulator, the evolution of which has contributed to increased complexity in the vertebrate nervous system.

Intracellular Bacterial Pathogens Trigger the Formation of U Small Nuclear RNA Bodies (U Bodies) through Metabolic Stress Induction

“…Although the mechanisms that control and coordinate the activity of the splicing machinery remain poorly defined, regulated expression of splicing-associated factors, such SF2/alternative splicing factor (42), polypyrimidine tract-binding proteins (43), or SR proteins (44), can affect splicing globally. In contrast, the synthesis and cytosolic maturation of U snRNPs, which represent essential building blocks of the spliceosome, are generally believed to be constitutively active and not subject to extensive cellular regulation, although a previous study showed that the activity of the SMN complex was regulated by oxidative stress (45).…”

Repair of pre-mRNA splicing

“…In the central nervous system (CNS), alternative splicing is particularly important, as it allows for the differentiation of neurons in several ways. [15][16][17][18] An interesting switch in the abundance of the splicing regulator polypyrimidine tract binding protein (PTB) to its neuronal counterpart nPTB represents an important trigger in neuronal their interactors. 11,12 In general, binding sites for SR proteins are more frequent in true exons, and hnRNP binding sites are more often found in introns.…”

Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor

“…From a single pre-mRNA species, multiple mRNA isoforms are generated by the shuffling of exons at intron-exon boundaries (17,18). By containing or excluding certain pre-mRNA sequences, different splicing isoforms of an encoded protein may exhibit distinct subcellular localizations, protein-protein association, and/or enzymatic activities.…”

“…By containing or excluding certain pre-mRNA sequences, different splicing isoforms of an encoded protein may exhibit distinct subcellular localizations, protein-protein association, and/or enzymatic activities. Recent studies indicate that nearly 95% of human multiexon genes undergo alternative splicing (17). Neurons, in particular, exhibit an unusually large number of functionally relevant alternative splicing events in which specific protein isoforms are produced to regulate a range of neuronal properties, including excitability, neurite outgrowth, and synaptic plasticity (18).…”