ERK Signaling in the Pituitary Is Required for Female But Not Male Fertility
Open accessAbstract
Males and females require different patterns of pituitary gonadotropin secretion for fertility. The mechanisms underlying these gender-specific profiles of pituitary hormone production are unknown; however, they are fundamental to understanding the sexually dimorphic control of reproductive function at the molecular level. Several studies suggest that ERK1 and -2 are essential modulators of hypothalamic GnRH-mediated regulation of pituitary gonadotropin production and fertility. To test this hypothesis, we generated mice with a pituitary-specific depletion of ERK1 and 2 and examined a range of physiological parameters including fertility. We find that ERK signaling is required in females for ovulation and fertility, whereas male reproductive function is unaffected by this signaling deficiency. The effects of ERK pathway ablation on LH biosynthesis underlie this gender-specific phenotype, and the molecular mechanism involves a requirement for ERK-dependent up-regulation of the transcription factor Egr1, which is necessary for LHβ expression. Together, these findings represent a significant advance in elucidating the molecular basis of gender-specific regulation of the hypothalamic-pituitary-gonadal axis and sexually dimorphic control of fertility.
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Other gonadotrope-specific genes (αGSU, FSHβ and GnRHR) are impacted when ERKs are specifically deleted in gonadotropes.
“Other gonadotrope-specific genes (αGSU, follicle stimulating hormone (FSH) β and the GnRHR) are also impacted when ERKs are specifically deleted in this cell type3,12.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [3]
In past studies, a pituitary-specific conditional ERK double knockout (ERKdko) was reported using ERK1 null and ERK2 floxed alleles combined with αGSU-Cre and GRIC drivers.
“In past studies, we reported a pituitary-specific conditional ERK double knockout (ERKdko) using the ERK1 null and ERK2 floxed alleles combined with a Cre recombinase driver regulated by the gene promoter for the α subunit to the glycoprotein hormones (αGSU)3,4 and the gonadotrope-specific Cre driver (GRIC)12,13.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [3]
The resultant phenotype of pituitary-specific ERKdko was female-specific anovulatory infertility due to loss of LH β subunit expression resulting in inability to mount a preovulatory surge of LH.
“The resultant phenotype was female-specific anovulatory infertility due to a loss of luteinizing hormone (LH) β subunit expression resulting in an inability to mount a preovulatory surge of LH.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [3]
Loss of ERK signaling within the gonadotrope is detrimental to the function of the hypothalamic-pituitary-gonadal axis and the placenta.
“While loss of ERK signaling within the gonadotrope has been shown to be detrimental to the function of the hypothalamic-pituitary-gonadal axis as well as the placenta”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [3]
This is the first report of a novel model of placental ERK gene deletion associated with expression of a GnRHR-Cre driver.
“this is the first report of a novel model of placental ERK gene deletion associated with expression of a GnRHR-Cre driver3,12,13”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [3]
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 [3]
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- Authors
- Bliss, S. P., Miller, A., Navratil, A. M., Xie, J., McDonough, S. P., Fisher, P. J., Landreth, G. E., & Roberson, M. S.
- Affiliations
- Cornell University (US)
- Department of Biomedical Sciences (S.P.B., A.M., A.M.N., J.X., S.P.M., P.J.F., M.S.R.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
- Case Western Reserve University (US)
- Corresponding author
- Roberson, Mark S.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-07-01
- Volume
- 23
- Issue
- 7
- Pages
- 1092-1101
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2703601
- OpenAlex
- W2099666698
- Cited by
- 91
- References
- 34
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 10 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 6 · 2012: 3
- FWCI
- 11.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD028934, R01 HD34722, R01HD034722, 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
- ERK signaling, ERK1/2, gonadotrophs, female fertility, male fertility, ovulation, hypothalamic-pituitary-gonadal axis
- MeSH terms
- Animals, Cells, Cultured, Female, Fertility, Male, Organ Specificity, Ovulation, Pituitary Gland, Superovulation, Thyroid Gland, Signal Transduction, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Luteinizing Hormone, beta Subunit, Extracellular Signal-Regulated MAP Kinases, Mitogen-Activated Protein Kinase 3, Mice
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