Gonadotrope Specific ERK Loss Causes Premature Reproductive Aging and Testicular Degeneration in Mice

Presentation Number: OR19-3
Date of Presentation: April 4th, 2017

Jessica L Brown*1, Jianjun Xie1, Jennifer L Sones2, Cynthia Angulo1, Andrew Miller1, Ulrich Boehm3 and Mark Stephen Roberson1
1Cornell College of Veterinary Medicine, Ithaca, NY, 2Lousiana State School of Veterinary Medicine, Baton Rouge, LA, 3University of Saarland School of Medicine, 66421 Homburg, Germany


Genetic ablation of extracellular-signal regulated kinase (ERK) 1 and 2 within the hypothalamic-pituitary-gonadal axis causes reproductive dysfunction. To understand the specific role for ERKs in the GnRH signaling network within gonadotropes, we utilized a conditional knockout mouse model. These mice were ERK1 null and ERK2 floxed combined with gonadotrope-specific Cre (GRIC) line. Additionally, these animals were studied as they matured to understand the role of ERK signaling in the gonadotrope during aging.

The ERK double knockout (ERKdko) females were infertile and anovulatory, with prolonged estrous cycles. ERKdko females were hypogonadotropic, with decreased levels of the gonadotropin subunit and GnRHR mRNA at estrus. ERKdko females had a blunted response to endogenous GnRH stimulation after castration. Aged females displayed abnormal ovarian histological architecture, with increases in extracellular matrix and marked areas of acellularity. This corresponded with reduced ovarian and uterine weights. Interestingly, the ERKdko female mice were significantly heavier as they aged, likely due to a decrease in energy expenditure for reproduction.

ERKdko males initially exhibited a less severe reproductive phenotype compared to females at 4 months. These males were moderately subfertile with decreased seminiferous tubule area and mildly decreased epididymal sperm count. Similar to females, they had a blunted response to endogenous GnRH following castration. The ERKdko males showed a precipitous decline in sperm count with age, losing almost 55 percent of sperm production between 4 and 12 months of age, and a total of 80 percent loss of sperm by 18 months. The control males in contrast, lost only 30 percent between 4 and 12 months, and 35 percent by 18 months. Consistent with these results, the ERkdko males had a decline in testicular weight, with no difference between the genotypes at 4 months, and a significant difference at 12 months of age. The testicular weight continued to decline in ERKdko animals at 18 months. The ERKdko males remained heavier than their control counterparts at all time points, and had significantly smaller seminal vesicles at both 12 and 18 months of age. Most strikingly, the ERKdko males had histological evidence of testicular degeneration including germ cell vacuolation, and degeneration/calcification of seminiferous tubules with increased age.

Characterizing these mice at several age points provides an entry towards understanding of the role of ERK1/2 signaling in pituitary gonadotropes throughout the lifespan of these animals. Specifically, we are not only able to analyze immediate effects of this ablation, but also characterize the long-term effects of hypogonadotropism and gonadotropin dysfunction on aging and senescence in mice. The premature aging displayed by the ERKdko males has potential implications for human and animal health.


Nothing to Disclose: JLB, JX, JLS, CA, AM, UB, MSR