Research Summary: We are interested in the role of posttranscriptional gene regulation during vertebrate development. Specifically, we want to understand the role of alternative splicing, which has recently gained more attention since it was discovered that the human genome has fewer, 23,425, protein coding genes. This observation was quite surprising when one considers that some of the invertebrate species such as the Drosophila (Fruit fly) has 14,000 protein coding genes. Thus, with an additional 10,000 genes one can make an entire human being. This raises the question as to how humans acquire the vast proteome complexity needed to build such a complex organism from so few genes. It is here that alternative splicing plays a vital role. Alternative splicing facilitates combinatorial splicing of exons to produce multiple protein isoforms from a single gene. Indeed, most vertebrate genes are now known to be alternatively spliced. Given the extent to which the genes are alternatively spliced, we want to understand how alternative splicing is regulated during development and the impact it may have in regulating gene networks during development. We employ mouse (mus musculus) as the primary model organism for our investigations. Moreover, it has been reported that amongst all the tissues, the central nervous system has the highest amount alternatively spliced transcripts. Thus, we employ the neural retinal to elucidate the role of Alternative Splicing in neural development.
Our current work has focused on the role of alternative splicing in regulating bHLH transcription factors during retinal development. Specifically, we have investigated the post-transcriptional regulation of one of the atonal homologues called Math5. We have found that this gene is a single exon gene, which is alternatively spliced to produce two isoforms. Interestingly, the major isoform is spliced such that the entire coding sequence is spliced out. Consequently, most of the RNA that is produced for Math5 cannot produce a functional protein. This raises several interesting questions, which will be the focus of our future investigations. First, why should retinal progenitor cells produce Math5-mRNA that does not code for protein? Second, does the non-coding isoform of Math5 have a function? Third, is this form of regulation found in other bHLH transcription factors?