Sex- and Age-Specific Impact of ERK Loss Within the Pituitary Gonadotrope in Mice
Open accessAbstract
Extracellular signal-regulated kinase (ERK) signaling regulates hormone action in the reproductive axis, but specific mechanisms have yet to be completely elucidated. In the current study, ERK1 null and ERK2 floxed mice were combined with a gonadotropin-releasing hormone receptor (GnRHR)–internal ribosomal entry site-Cre (GRIC) driver. Female ERK double-knockout (ERKdko) animals were hypogonadotropic, resulting in anovulation and complete infertility. Transcript levels of four gonadotrope-specific genes (GnRHR and the three gonadotropin subunits) were reduced in pituitaries at estrus in ERKdko females, and the postcastration response to endogenous GnRH hyperstimulation was blunted. As females aged, they exhibited abnormal ovarian histology, as well as increased body weight. ERKdko males were initially less affected, showing moderate subfertility, up to 6 months of age. Male ERKdko mice also displayed a blunted response to endogenous GnRH following castration. By 12 months of age, ERKdko males had reduced testicular weights and sperm production. By 18 months of age, the ERKdko males displayed reduced testis and seminal vesicle weights, marked seminiferous tubule degeneration, and a 77% reduction in sperm production relative to controls. As the GRIC is also active in the male germ line, we examined the specific role of ERK loss in the testes using the stimulated by retinoic acid 8 (Stra8)-Cre driver. Whereas ERK loss in GRIC and Stra8 males resulted in comparable losses in sperm production, seminiferous tubule histological degeneration was only observed in the GRIC-ERKdko animals. Our data suggest that loss of ERK signaling and hypogonadotropism within the reproductive axis impacts fertility and gonadal aging.
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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 [12]
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 [12]
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 [12]
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 [12]
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References 52 · Cited by 14
Research works printed but not linked: 1
- Cushman LJ, Burrows HL, Seasholtz AF, Lewandoski M, Muzyczka N, Camper SA. Cre-mediated recombination in the pituitary gland. Genesis. 2000;28(3-4):167-174.
- Authors
- Brown, J. L., Xie, J., Brieño-Enriquez, M. A., Sones, J., Angulo, C. N., Boehm, U., Miller, A., Toufaily, C., Wang, Y., Bernard, D. J., & Roberson, M. S.
- Affiliations
- Cornell University (US)
- Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York
- Saarland University (DE)
- McGill University (CA)
- Corresponding author
- Roberson, Mark S
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2018-01-03
- Volume
- 159
- Issue
- 3
- Pages
- 1264-1276
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC5802804
- OpenAlex
- W2782504021
- Cited by
- 14
- References
- 52
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 1
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD034722, R21 HD082780)
- Canadian Institutes of Health Research (MOP-123447)
- Natural Sciences and Engineering Research Council of Canada (2015-05178)
- 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, GnRH receptor, hypogonadotropic hypogonadism, anovulation, infertility, spermatogenesis, seminiferous tubule degeneration, testis, ovary, sex differences, reproductive axis
- MeSH terms
- Age Factors, Animals, Anovulation, Estrenes, Female, Fertility, Genotype, Gonadotropins, Pituitary, Hypogonadism, Infertility, Male, Organ Size, Ovary, Receptors, LHRH, Reproduction, RNA, Messenger, Sex Factors, Sulfonic Acids, Testis, Mice, Knockout, MAP Kinase Signaling System, Mice, Gonadotrophs
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