FOXL2 in the pituitary: molecular, genetic, and developmental analysis.
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 alpha-subunit (alphaGSU) 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 alphaGSU suggested that the alphaGSU gene (Cga) is a downstream target of FOXL2. We demonstrate that FOXL2 regulates mouse Cga transcription in gonadotrope-derived (alphaT3-1, LbetaT2), thyrotrope-derived (alphaTSH) 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.
Ellsworth
Buffy S
BS
The University of Michigan Medical School, 4909 Buhl Building, Ann Arbor, Michigan 48109-0618, USA.
Egashira
Noboru
N
Haller
Jodi L
JL
Butts
Darcy L
DL
Cocquet
Julie
J
Clay
Colin M
CM
Osamura
Robert Y
RY
Camper
Sally A
SA
D000818:Animals; D004622:Embryo, Mammalian; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D015292:Glycoprotein Hormones, alpha Subunit / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010902:Pituitary Gland / Q000196:embryology* / Q000378:metabolism*; D010903:Pituitary Gland, Anterior / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D015292:Glycoprotein Hormones, alpha Subunit; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; C108538:Lhx4 protein, mouse; D014157:Transcription Factors