However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms control- ling FSH synthesis. Previously, we discovered a critical role for fork- head protein L2 (FOXL2) in activin-stimulated FSH B-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hy- pothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Fox/2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice de- veloped overtly normally but were subfertile in adulthood. Testis size and spermatogenesis were significantly impaired in cKO males. cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls. In con- trast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation. Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production. Basal and activin-stimulated Fshb expression was similarly impaired in Fox/2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first iden- tified gonadotrope-restricted transcription factor required for se- lective FSH synthesis in vivo.
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