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摘要
Multiple homeodomain transcription factors are crucial for pituitary organogenesis and cellular differentiation. A homeodomain repressor, Msx1, is expressed from the ventral aspect of the developing anterior pituitary and implicated in gonadotrope differentiation. Here, we find that Msx1 represses transcription of lineage-specific pituitary genes such as the common alpha-glycoprotein subunit (alpha GSU) and GnRH receptor (GnRHR) promoters in the mouse gonadotrope-derived cell lines, alpha T3-1 and L beta T2. Repression of the mouse GnRHR promoter by Msx1 is mediated through a consensus-binding motif in the downstream activin regulatory element (DARE). Truncation and mutation analyses of the human alpha GSU promoter map Msx1 repression to a site at -114, located at the junctional regulatory element (JRE). Dlx activators are closely related to the Msx repressors, acting through the same elements, and Dlx3 and Dlx2 act as transcriptional activators for GnRHR and alpha GSU, respectively. Small interfering RNA knockdown of Msx1 in alpha T3-1 cells increases endogenous alpha GSU and GnRHR mRNA expression. Msx1 gene expression reaches its maximal expression at the rostral edge at e 13.5. The subsequent decline in Msx1 expression specifically coincides with the onset of expression of both alpha GSU and GnRHR. The expression levels of both alpha GSU and GnRHR in Msx1-null mice at e 18.5 are higher compared with wild type, further confirming a role for Msx1 in the repression of alpha GSU and GnRHR. In summary, Msx1 functions as a negative regulator early in pituitary development by repressing the gonadotrope-specific alpha GSU and GnRHR genes, but a temporal decline in Msx1 expression alleviates this repression allowing induction of GnRHR and alpha GSU, thus serving to time the onset of gonadotrope-specific gene program. (Molecular Endocrinology 27: 422-436, 2013)
- 出版日期2013-3
