| First Author | Xie H | Year | 2013 |
| Journal | Mol Endocrinol | Volume | 27 |
| Issue | 3 | Pages | 422-36 |
| PubMed ID | 23371388 | Mgi Jnum | J:321038 |
| Mgi Id | MGI:6874923 | Doi | 10.1210/me.2012-1289 |
| Citation | Xie H, et al. (2013) Msx1 homeodomain protein represses the alphaGSU and GnRH receptor genes during gonadotrope development. Mol Endocrinol 27(3):422-36 |
| abstractText | 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 (alphaGSU) and GnRH receptor (GnRHR) promoters in the mouse gonadotrope-derived cell lines, alphaT3-1 and LbetaT2. 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 alphaGSU 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 alphaGSU, respectively. Small interfering RNA knockdown of Msx1 in alphaT3-1 cells increases endogenous alphaGSU and GnRHR mRNA expression. Msx1 gene expression reaches its maximal expression at the rostral edge at e13.5. The subsequent decline in Msx1 expression specifically coincides with the onset of expression of both alphaGSU and GnRHR. The expression levels of both alphaGSU and GnRHR in Msx1-null mice at e18.5 are higher compared with wild type, further confirming a role for Msx1 in the repression of alphaGSU and GnRHR. In summary, Msx1 functions as a negative regulator early in pituitary development by repressing the gonadotrope-specific alphaGSU and GnRHR genes, but a temporal decline in Msx1 expression alleviates this repression allowing induction of GnRHR and alphaGSU, thus serving to time the onset of gonadotrope-specific gene program. |
