Impaired Fertility and FSH Synthesis in Gonadotrope-Specific Foxl2 Knockout Mice
Open accessAbstract
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.
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Although multiple mouse models have been used to recapitulate idiopathic hypogonadal hypogonadism (IHH), none have focused on loss of function in cells expressing GnRHR and how ERK signaling may be functioning in these tissue compartments.
“Although multiple mouse models have been used to recapitulate idiopathic hypogonadal hypogonadism (IHH), none have focused on loss of function in cells expressing GnRHR and how ERK signaling may be functioning in these tissue compartments3,64,65.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [64]
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- Authors
- Tran, S., Zhou, X., Lafleur, C., Calderon, M. J., Ellsworth, B. S., Kimmins, S., Boehm, U., Treier, M., Boerboom, D., & Bernard, D. J.
- Affiliations
- McGill University (CA)
- Southern Illinois University Carbondale (US)
- Saarland University (DE)
- Max Delbrück Center (DE)
- Université de Montréal (CA)
- Corresponding author
- Bernard, Daniel J.
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-03-01
- Volume
- 27
- Issue
- 3
- Pages
- 407-421
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC3589670
- OpenAlex
- W2079682188
- Cited by
- 74
- References
- 93
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 8
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP89991)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD028934, R15HD063469, U54-HD-28934)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- FOXL2, FSH beta subunit, gonadotrophs, anterior pituitary, infertility, spermatogenesis, activin signaling, transcription factors, conditional knockout mice, gonadotropin deficiency
- MeSH terms
- Forkhead Box Protein L2, Animals, Female, Fertility, Gene Expression Regulation, Gonadotropins, Ovarian Follicle, Horses, Humans, Male, Organ Specificity, Organ Size, Ovulation, Recombination, Genetic, RNA, Messenger, Sertoli Cells, Spermatogenesis, Testis, Gene Deletion, Mice, Knockout, Activins, Follicle Stimulating Hormone, beta Subunit, Mice, Forkhead Transcription Factors, Gonadotrophs, Genetic Loci
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