The primary objective of this proposal is to understand the molecular mechanisms that regulate female reproductive tract organogenesis. Our preliminary studies indicate that the homeobox gene Lim1 and the gene encoding the Mullerian inhibiting substance type II receptor Misr2 provide molecular entry points for dissecting the genetic pathways that regulate Mullerian duct epithelium and mesenchyme development, respectively, for female reproductive tract formation. We propose molecular genetic studies to 1) visualize the cellular behavior of Mullerian duct epithelium and mesenchyme during Mullerian duct formation using time lapse imaging of differentially colored nuclear- and mitotic chromosome-tagged fluorescent proteins, 2) identify the cis-elements of the Lim1 and Misr2 genes that direct Mullerian duct epithelium- and mesenchyme-specific transcription, respectively, 3) examine the role of the Wolffian duct in Mullerian duct formation, 4) determine the role of Lim1 in female reproductive tract formation, and 5) define the signaling molecules that act in mesenchyme to mediate Mullerian inhibiting substance-induced Mullerian duct regression using a novel conditional knockout strategy. Our proposed studies should provide new information about the molecular and cellular mechanisms that regulate female reproductive tract formation and its elimination during male fetal development.
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