Cited by 74Hypothalamic control of reproductive hormonesReproductive Biology and FertilitySperm and Testicular Function

Impaired Fertility and FSH Synthesis in Gonadotrope-Specific Foxl2 Knockout Mice

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Tran, Stella, Zhou, Xiang, Lafleur, Christine, Calderon, Michael J., Ellsworth, Buffy S., Kimmins, Sarah, Boehm, Ulrich, Treier, Mathias +2 more·2013·Molecular Endocrinology

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.

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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.”

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  1. [24]24. Dalkin AC, Burger LL, Aylor KW, et al. Regulation of gonadotropin subunit gene transcription by gonadotropin-releasing hormone: measurement of primary transcript ribonucleic acids by quantitative reverse transcription-polymerase chain reaction assays. Endocrinology. 2001;142:139–146 [DOI] [PubMed] [Google Scholar]

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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.
Venue
Molecular Endocrinology
Published
2013-03-01
Volume
27
Issue
3
Pages
407-421
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
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
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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