MRG1 Binds to the LIM Domain of Lhx2 and May Function as a Coactivator to Stimulate Glycoprotein Hormone α-Subunit Gene Expression

Abstract

Members of the LIM homeodomain family of transcription factors have been shown to contribute to the regulated expression of the ␣-subunit of the glycoprotein family of hormones (1). The ability of the pituitary to secrete the gonadotropic hormones, follicle-stimulating hormone, and luteinizing hormone is crucial for normal reproductive function. The synthesis and secretion of the gonadotropins is regulated by the hypothalamic hormone, gonadotropin-releasing hormone (GnRH), 1 which acts to increase gonadotropin subunit mRNA levels (2-9) through effects at the transcriptional level (10, 11).LIM homeodomain factors appear to play a role in both basal and GnRH-stimulated expression of the glycoprotein hormone ␣-subunit gene (1, 12). Initial studies demonstrated that LIM homeodomain factor-2 (Lhx2, also designated LH-2) can bind to a pituitary-specific enhancer element designated the PGBE of the mouse ␣-subunit gene (1). Because both the PGBE and a separate, structurally distinct DNA element designated the GnRH-RE are required for GnRH responsiveness of the mouse glycoprotein hormone ␣-subunit promoter (12), the finding that Lhx2 binds to the PGBE implies that this LIM factor plays a role in transcriptional responses to GnRH. It has also been shown that a related LIM factor, Lhx3 (also designated pLIM or LIM3) can also enhance ␣-subunit gene expression (13). Targeted disruption of the Lhx3 gene in mouse results in loss of pituitary organogenesis (14), demonstrating that LIM factors also play an important developmental role in the formation of the pituitary.The specific role that the LIM domains play in transcriptional activation is somewhat unclear. The LIM domain, named for the genes of the first three members of the family, lin-11 (15), isl-1 (16), and mec-3 (17), is characterized by the presence of two zinc finger motifs that involve cysteine and histidine or aspartate residues that tetrahedrally coordinate a zinc atom (18,19). There is evidence that some LIM domains can inhibit DNA binding of the associated homeodomain (20 -22). This would suggest that the LIM domain may negatively regulate LIM factor activity. However, it is not clear that inhibition of DNA binding is a general phenomenon for LIM factors (23). Functional studies of Xlim-1 in Xenopus laevis have shown that deletion or mutation of the LIM domain of Xlim-1 results in the induction of secondary axis formation, whereas the wild type factor has no effect (24). This has been interpreted as evidence for a negative role for the LIM domain in regulating transcription. However, in the absence of more mechanistic information about Xlim-1 action, other interpretations are possible. In contrast to the view that LIM domains play a negative role in regulating DNA binding and transcription, some LIM factors have been shown to demonstrate synergistic transcriptional activation with other transcription factors (13,25).Recently, a putative co-activator was identified independently in several labs that binds to members of the LIM homeodomain protein family and nucle...

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