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An Otx-Related Homeodomain Protein Binds an LHß Promoter Element Important for Activation During Gonadotrope Maturation

Department of Reproductive Medicine (S.B.R., P.L.M.) and Neurosciences (P.L.M.), University of California, San Diego, La Jolla, California 92093-0674

Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine 0674, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}ucsd.edu.

The hormone-secreting cell types of the anterior pituitary differentiate in a specific spatial and temporal manner. The -subunit of the glycoprotein hormones appears at embryonic d 11.5 in the mouse, followed by steroidogenic factor-1, which distinguishes the gonadotrope progenitor cells, around embryonic d 14. Gonadotrope maturation is marked by the onset of LHß-gene expression 2 d later. The T3-1 and LßT2 immortalized mouse pituitary cell lines correspond to these later sequential stages of gonadotrope differentiation. In addition to the early markers of the gonadotrope lineage present in T3-1 cells, LßT2 cells also express markers of a mature gonadotrope, including LHß and FSHß. Using transient transfections to compare expression among gonadotrope and nongonadotrope-derived cell types, we show that the rat 1.8-kb LHß promoter directs reporter gene expression specifically to the mature gonadotrope LßT2 cell line. Promoter truncation and mutagenesis analyses indicate that the homeodomain (HD) element located at approximately -100 bp relative to the transcriptional start site is essential for this selectivity to LßT2 cells when compared with T3-1 cells. In EMSAs, this HD site binds a protein present in LßT2 but not other gonadotrope-derived cells. Antibody supershift and competition experiments indicate that this LßT2 nuclear protein is a K50 HD protein related to the Otx family, though it is not a known pituitary homeobox transcription factor protein. These studies indicate a role for a novel Otx-related HD protein in gonadotrope maturation during development.

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