Gonadotrope-Specific Ablation of JNK1/2 Reveals an Inhibitory Role in FSHβ Synthesis In Vivo

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

Brian S Edwards*1, Shaihla Amin Khan1, Ulrich Boehm2, Roger J Davis3 and Amy Marie Navratil1
1University of Wyoming, Laramie, WY, 2University of Saarland School of Medicine, 66421 Homburg, Germany, 3HHMI/UMASS Med Schl, Worcester, MA


Gonadotropin releasing hormone receptor (GnRHR) activation 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 has highlighted an important role for the c-Jun NH2-terminal kinase (JNK) signaling cascade in regulating both GnRHR expression levels and pulsatile LH secretion; events that are essential for reproductive viability. However, whether JNK regulates fertility at the level of the pituitary in vivo is currently unknown. To specifically address this question, we utilized Cre/loxP technology to selectively inactivate JNK 1 and JNK 2 (JNK 1/2) in gonadotrope cells of the anterior pituitary (DKO). Conditional knockout of floxed JNK 1/2 alleles in gonadotropes was accomplished using the previously described GRIC mouse strain, which coexpresses the GnRHR with Cre recombinase. qPCR analyses revealed an increase in FSHβ mRNA levels in both DKO males and females. Consistent with elevated pituitary FSHβ transcript levels, serum FSH levels were also significantly increased in DKO animals in both genders when compared to controls. Additionally, pituitary expression of GnRHR and LHβ were increased in DKO females along with serum LH levels; indicating that LH concentration may be linked to enhanced GnRHR expression. Consistent with elevated serum FSH levels, DKO females had increased ovarian weights due to enhanced folliculogenesis. Furthermore, DKO females exhibited altered estrous cyclicity, which resulted in significantly increased time to first pregnancy. Lastly, our results suggest that the mechanistic actions of JNK regulation of FSH is through activin signaling at the level of SMADs. Taken together, our results reveal a novel inhibitory role for JNK signaling in gonadotrope regulation of FSHβ synthesis in vivo.


Nothing to Disclose: BSE, SAK, UB, RJD, AMN