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Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.06.023 Byline: Benjamin J. Blencowe (1) Abstract: Recent analyses of sequence and microarray data have suggested that alternative splicing plays a major role in the generation of proteomic and functional diversity in metazoan organisms. Efforts are now being directed at establishing the full repertoire of functionally relevant transcript variants generated by alternative splicing, the specific roles of such variants in normal and disease physiology, and how alternative splicing is coordinated on a global level to achieve cell- and tissue-specific functions. Recent progress in these areas is summarized in this review. Author Affiliation: (1) Banting and Best Department of Medical Research and Department of Molecular and Medical Genetics, Centre for Cellular and Biomolecular Research, Donnelly CCBR Building, University of Toronto, 160 College Street, Room 1016, Toronto, ON M5S 3E1, Canada

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.03.010 Byline: Mathieu Gabut, Sidharth Chaudhry, Benjamin J. Blencowe