Gonadotrope Specific Ablation of JNK 1/2 Leads to Impaired Fertility

Zukauckas, Kelsea N.
Gonadotropin releasing hormone (GnRH) activation of gonadotrope cells initiates an intricate network of signaling pathways that results in the synthesis and secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), from the anterior pituitary. Previous work highlighted an important role for the c-Jun NH2-terminal kinase (JNK) signaling cascade in regulating GnRH receptor (GnRHR) expression levels and pulsatile secretion of LH; essential events for reproductive viability. Awaiting systematic clarification are the in vivo requirements of JNK in the regulation of fertility at the level of the pituitary. To specifically address this, we utilized cre/lox technology to selectively knockout JNK 1 and JNK 2 (JNK 1/2) in the gonadotrope (JNK DKO). Conditional knockout of transgenic C57BL/6 mice with floxed JNK 1/2 alleles was accomplished using the previously described GRIC mouse, in which expression of Cre recombinase is coexpressed with the GnRHR gene. Estrous stage cycling revealed that JNK DKO females had irregular cycles, marked by prolonged diestrus and abnormal cycle length that ranged to upwards of 9 days. Consistent with abnormal cyclicity, our initial breeding experiments showed that JNK DKO females paired with a CRE-negative male had significantly reduced litters from control animals. Litter sizes were similarly reduced when control CRE-negative females were paired with JNK DKO males suggesting reproductive deficits may also occur in males. Collectively, our results reveal that ablation of JNK1/2 expression impairs the timing of ovulation, and functional JNK activity is important for fertility in both females and males.
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