Alternative Splicing in the Mammalian Nervous System

Alternative splicing is widely considered to be a major mechanism underlying the evolution of increased cellular and functional complexity in vertebrate species and is especially prevalent in the mammalian nervous system. Microarray profiling and, more recently, high‐throughput sequencing has resulted in the identification of a myriad of nervous system‐regulated exons. Many of these are located in widely expressed genes that have critical nervous system‐specific functions. Our research is currently focusing on elucidating the cis ‐acting "code" and corresponding trans‐acting factors responsible for the regulation of these exons, and their specific roles in nervous system formation and function. In collaboration with the group of Brendan Frey (Dept. of Electrical and Computer Engineering, University of Toronto) we have developed a new machine learning algorithm that can predict nervous system and other tissue‐regulated alternative splicing patterns from sequence features alone. Using other genome‐wide strategies as well as focused experimental methods we are identifying and characterizing trans ‐acting factors that link to specific elements of the cis ‐regulatory code. A new trans ‐acting factor emerging from one of the screens is the neural‐specific SR‐related protein of 100 kDa (nSR100). This protein is vertebrate‐lineage‐specific and functions as a coactivator to regulate ~10‐12% of nervous‐system specific exons via C/U‐rich motifs concentrated in flanking intron sequences. Knockdown of this protein disrupts the regulation of a network of alternative exons associated with neuronal differentiation and nervous system development.