The Role of Transcription Factor Isoforms in Eye and Neural Crest Development

Neurological Disorders And Stroke

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Abstract

Alternative splicing, by which protein isoforms differing in sequence and in function can be generated from a single gene, is a mechanism important for the regulation of most if not all aspects of biology. Not surprisingly, splicing alterations are critical contributors to pathogenesis. We are currently studying alternative splicing in the transcription factor gene Mitf. This gene regulates the formation of pigment cells from the neural crest and the neuroepithelium of the eye and serves as an excellent model for assessing the biological significance of alternative splicing. We have generated a line of mice in which a change in an exonic sequence leads to a splicing alteration that eliminates the corresponding exon. Interestingly, the altered proteins affect cell proliferation differently compared to wild type. To dissect the underlying mechanisms, we have analyzed the cell proliferation parameters by FACS analysis and are studying the splicing defects in transfected minigenes. The studies indicate that the mutant minigenes recapitulate the splicing defects seen in the mutant mice and show that serine-arginine-rich splicing proteins, called SR proteins, enhance or suppress the splicing defect not only in the minigenes but also in the endogenous gene. Hence, by focusing on MITF and SR proteins, we have identified an interplay between splicing and cell proliferation, and we are currently focusing on the question of potential feed back loops that might exist between the two processes.