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FOXL2 in the Pituitary: Molecular, Genetic, and Developmental Analysis

Department of Human Genetics (B.S.E., D.L.B., S.A.C.), The University of Michigan, Ann Arbor, Michigan 48109-0638; Department of Pathology (N.E., R.Y.O.), Tokai University, Isehara, Kanagawa 259-1193, Japan; Animal Reproduction and Biotechnology Laboratory (J.L.H., C.M.C.), Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523; and Institut National de la Santé et de la Recherche Médicale Unité 709 (J.C.), Reproduction et Physiopathologie Obstetricale, Hopital Cochin, Paris, France 75014

Address all correspondence and requests for reprints to: Sally A. Camper, The University of Michigan Medical School, 4909 Buhl Building, Ann Arbor, Michigan 48109-0618. E-mail: scamper{at}umich.edu

FOXL2 is a forkhead transcription factor expressed in the eye, ovary, and pituitary gland. 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 colocalizes with the glycoprotein hormone -subunit (GSU) in quiescent cells of the mouse pituitary from embryonic d 11.5 through adulthood. FOXL2 is expressed in essentially all gonadotropes and thyrotropes and a small fraction of prolactin-containing cells during pregnancy, but not somatotropes or corticotropes. The coincident expression patterns of FOXL2 and GSU suggested that the GSU gene (Cga) is a downstream target of FOXL2. We demonstrate that FOXL2 regulates mouse Cga transcription in gonadotrope-derived (T3-1, LßT2), thyrotrope-derived (TSH) and heterologous (CV-1) cells in a context-dependent manner. In addition, a FOXL2-VP16 fusion protein is sufficient to stimulate ectopic Cga expression in transgenic animals. Normal FOXL2 expression requires the transcription factors Lhx3 and Lhx4 but not of Prop1. Thus, FOXL2 expression is affected by mutations in early pituitary developmental regulatory genes, and its expression precedes that of genes necessary for gonadotrope-specific development such as Egr1 and Sf1 (Nr5a1). These data place FOXL2 in the hierarchy of pituitary developmental control and suggest a role in regulation of Cga gene expression.

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