Transcriptional regulation by WT1-BASP1 complex and the role of WT1 in taste cell development
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The Wilms's tumor 1 gene (WT1) encodes a zinc finger transcription factor that directs the development of several organs and tissues. As a transcriptional regulator, WT1 can either activate or repress numerous target genes resulting in disparate biological effects on growth, differentiation and apoptosis. The transcriptional corepressor BASP1 interacts with WT1 and converts WT1 from an activator to a repressor of transcription. The mechanisms by which BASP1 acts as a transcriptional corepressor were not known. I have sought to identify cofactors of the WT1-BASP1 complex that are required to mediate transcriptional repression, and to determine the mechanisms of transcriptional repression by WT1-BASP1 complex. My first findings uncover a previously unknown role for myristoylation in transcription and a critical function for phospholipids in gene-specific transcriptional repression through the recruitment of histone deacetylase. I then characterized the transcriptional repressor prohibitin as part of the WT1-BASP1 transcriptional repression complex and the mechanism by which prohibitin mediates transcriptional repression of WT1 target genes. It is noteworthy that WT1 has been detected in populations of neurons in the brainstem and spinal cord. WT1 is also necessary for neuronal development in the vertebrate retina and the olfactory system. These findings raised the interesting possibility that WT1 might also be involved in the development of a third sensory system: the taste peripheral system. Indeed, our findings demonstrate that WT1 is critical for normal taste cell development and regulates genes that encode proteins associated with the developing taste system such as PTCH1, the receptor for Sonic hedgehog (SHH), LEF1 a component of the Wnt-signaling pathway and BMP4. Thus, primary taste cells could be used to study the function of WT1 and its cofactors. For this reason, the long term-maintenance and transfections of primary taste cells in culture were standardized as a model to study WT1 function.