Sex- and Age-Specific Impact of ERK Loss Within the Pituitary Gonadotrope in Mice

Jessica L. Brown, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Jianjun Xie, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Miguel Angel Brieño-Enriquez, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Jennifer L. Sones, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Cynthia N. Angulo, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Ulrich Boehm, Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany.
Andrew Miller, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Chirine Toufaily, Department of Pharmacology and Therapeutics, McGill University, Québec, Canada.
Ying Wang, Department of Pharmacology and Therapeutics, McGill University, Québec, Canada.
Daniel J. Bernard, Department of Pharmacology and Therapeutics, McGill University, Québec, Canada.
Mark S. Roberson, Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York.

Abstract

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.