LIM Homeodomain Factors and Pituitary Gene Expression

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The overall goal is to understand the roles that specific LIM homeodomain (Lhx) transcription factors play in expression of the glycoprotein hormone subunit genes in thyrotropes and gonadotropes of the pituitary and to determine the mechanism of action of Lhx factors. We have shown that Lhx2 and Lhx3 can interact with a specific DNA element designated the PGBE to activate transcription of the glycoprotein hormone alpha-subunit gene. These findings raise the possibility that Lhx2 and Lhx3 may play an interchangeable role in regulating alpha-subunit gene expression. However, recent findings from this and other laboratories suggest specificity in Lhx factor action. We have recently performed a mutational study that offers evidence for distinct mechanisms mediating transcriptional responses to Lhx2 and Lhx3. The possibility of distinct actions of individual Lhx factors is consistent with recent studies of the role of specific Lhx factors in central nervous system development. Although the Lhx2 and Lhx3 genes have been disrupted in mice, the genetic manipulations result in developmental defects so that adult populations of pituitary cells are not available. To address these issues and explore the mechanism of Lhx factor action the specific aims include: 1) Map the site of GnRH-induced phosphorylation of Lhx2 and Lhx3 and evaluate the function of this phosphorylation. The possibility of GnRH-induced phosphorylation of SLB will also be evaluated. 2) Use a genetic screen to identify mutations that disrupt the interaction between Lhx3 and the putative adapter/coactivator, SLB, to examine structurefunction relationships for this complex in alpha-subunit gene expression. 3) Directly test the requirement for Lhx2, Lhx3 and SLB for alpha-subunit gene expression in vivo. 4) Search for Lhx2 and Lhx3 target genes. These studies should define the role of specific Lhx factors in gonadotropin and thyrotropin biosynthesis as well as provide new insights into more general issues about specificity and mechanisms mediating Lhx actions to regulate gene expression and development.