PARENT SESSION

(109) THE FORKHEAD FACTOR, FOXL2, REGULATES EXPRESSION OF THE GLYCOPROTEIN HORMONE ALPHA SUBUNIT (GSU).

Ellsworth, Buffy¹, Egashira, Noboru^{1, 2}, Osamura, Robert², Camper, Sally¹, ¹ The University of Michigan, Ann Arbor, MI² Tokai University, Isehara, Kanagawa, Japan

ABSTRACT- The forkhead family of transcription factors plays critical roles in diverse developmental processes and human disease. FOXL2 is a forkhead factor expressed in the eye, ovary and pituitary. Loss of function mutations in humans and mice confirm a functional role for FOXL2 in the eye and ovary, but its role in the pituitary is not yet defined. We report that FOXL2 is present in quiescent cells of the developing mouse pituitary by e12.5 and is persistently expressed in adult pituitary in gonadotrope and thyrotrope cells. It is not expressed in somatotropes or corticotropes, but does co-localize with a small fraction of prolactin-containing cells during pregnancy. PRL co-localizes with TSH, but not LH in pituitaries from pregnant mice suggesting that thyrotropes are transdifferentiating into lactotropes during pregnancy and that FOXL2 expression is present only as a lingering thyrotrope trait. Consistent with FOXL2 expression in gonadotropes and thyrotropes, both of which express GSU, FOXL2 and GSU co-localize from e12.5 through adulthood. Based on their similar expression patterns we hypothesize that FOXL2 regulates expression of the reproductively essential GSU (Cga) gene. Several families of transcription factors are known to regulate the Cga promoter in cell culture, including GATA, SF1, LIM and PITX, but the role of FOXL2 has not been explored. We report that the mouse Cga promoter is stimulated by FOXL2 approximately 3-fold in T3-1 cells, and the responsive region maps between −341 and −297 bp. This region is important for Cga expression in cell culture and cell-specific expression in mice. This region contains a consensus forkhead binding site and a LIM heomeodomain factor-binding site. Thus, FOXL2 may interact with a member of the LIM family to regulate Cga expression. No direct targets have been identified for FOXL2 in the ovary or the eye, however FOXL2 does regulate another pituitary gene, the GnRH receptor gene (Gnrhr), which is also essential for reproduction. Understanding the mechanism of FOXL2 regulation of pituitary genes may give us insight into FOXL2 regulation of ovary and eye development. Further studies in transgenic animals will be valuable for assessing the requirement for FOXL2 in Cga and Gnrhr expression and for revealing new genes that are regulated by FOXL2.

KEY WORDS: FOXL2, pituitary, alphaGSU, development