Mullerian Inhibiting Substance (MIS) is a member of the large transforming growth factor-beta multigene family which is involved in the regulation of growth and differentiation. The expression of MIS, a unique growth inhibitory hormone, is highly tissue specific and tightly regulated temporally. The cell-type and age specificity of MIS expression is likely to be governed by differential transcription of the MIS gene. This novel pattern of expression, then, would be modulated by interactions between specific trans-acting factors and cis regulatory elements. Therefore, as a prototypic growth inhibitory hormone, with strictly regulated and sexually dimorphic patterns of expression, MIS is an excellent model for studying the basic biology of gene regulation. The transcriptional regulatory mechanisms underlying the expression of this unique hormone have not yet been systemically studied. The focus of this proposal is to investigate the gene control of MIS by characterizing and precisely identifying the cis-acting elements that confer its sexually dimorphic tissue and age specific pattern of expression. To examine critical protein-DNA interactions, mobility shift assays with DNA fragments of the MIS 5' flanking region will be conducted. To identify functional regulatory elements of MIS, primary and established cell lines will be transfected with fusion genes of mutated MIS promoter/enhancer sequences linked to a reporter gene. The parallel strategies for examining the transcriptional regulation of MIS will yield complementary information to extend the current understanding of hormone gene control. Understanding the mechanisms underlying the expression of MIS will provide insights on the basic biology of gene regulation and on the control of growth and differentiation processes.
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