This application focusses on regulation and function of the mouse proneural gene MASH-1. MASH-1 encodes a DNA binding protein of the bHLH family; its expression and loss of function phenotype has been studied extensively. During the previous granting period the applicant has set out to identify cis- and transacting factors controlling MASH-1 expression in the mouse nervous system. These efforts resulted in the identification of a 1.2kB sequence which is able to drive a lacZ reporter gene in a pattern similar to that one of endogenous MASH-1 expression. The location of relevant cis-acting elements has been further narrowed down by deletion constructs; three 150bpp regions were identified within the 1.2kB piece whose deletion led to significant losses of part of the lacZ expression. It was also discovered that expression of the reporter constructs is upregulated in homozygous MASH-1 mutant background, suggesting that MASH-1 protein may act as an inhibitor of its own expression. Finally, the applicant has furnished convincing preliminary evidence that, contrary to prior reports, MASH-1 knockout mice show significant defects in the CNS.
Aims 1 -3 of this proposal intend to identify specific binding sites for transcription factors in the 1.2kB MASH-1 mutant brains.
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