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Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice
Stella Tran1, Xiang Zhou, Christine Lafleur
1Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
Abstract:
Impairments in pituitary FSH synthesis or action cause infertility. However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis. Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH β-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice developed 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 contrast, 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 Foxl2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo.
Insights
Forkhead protein L2 (FOXL2) is essential for follicle-stimulating hormone (FSH) synthesis in vivo. Ablating FOXL2 in mice impairs FSH production, leading to infertility and reproductive issues in both sexes.
Area of Science:
- Endocrinology
- Reproductive Biology
- Molecular Genetics
Background:
- Pituitary follicle-stimulating hormone (FSH) is crucial for fertility.
- Mechanisms regulating FSH synthesis are not fully understood.
- Forkhead protein L2 (FOXL2) was previously implicated in FSH subunit gene transcription in vitro.
Purpose of the Study:
- To investigate the in vivo requirement of FOXL2 for FSH synthesis.
- To determine the role of FOXL2 in gonadotrope cells for reproductive function.
Main Methods:
- Conditional knockout (cKO) mouse model using Cre/lox technology to ablate Foxl2 in anterior pituitary gonadotrope cells.
- Assessment of reproductive parameters, including fertility, testis size, spermatogenesis, ovarian weight, and oocyte ovulation.
- Analysis of FSH beta subunit (Fshb) mRNA expression in pituitary tissues and primary cell cultures.
Main Results:
- Conditional knockout mice exhibited subfertility, impaired spermatogenesis, reduced testicular size, and decreased ovarian weight.
- cKO females showed reduced oocyte ovulation during natural estrous cycles.
- FSH deficiency was observed in both male and female cKO mice due to diminished pituitary Fshb mRNA production.
- Impaired Fshb expression was noted in both basal and activin-stimulated primary pituitary cultures from Foxl2-depleted mice.
Conclusions:
- FOXL2 is definitively established as the first gonadotrope-restricted transcription factor essential for selective FSH synthesis in vivo.
- FOXL2 plays a critical role in regulating FSH production and maintaining reproductive function.
