Stress, mixed messages, and hormone signaling: Regulation of translation and the unfolded protein response in pituitary gonadotropes.

摘要

The reproductive axis is controlled by release of GnRH from the hypothalamus, which stimulates gonadotrope cells in the anterior pituitary to activate and maintain the synthesis of one of their main secretory outputs, luteinizing hormone (LH). While the transcriptional regulation of the subunits of LH is well described, very little work has focused on the post-transcriptional regulatory pathways induced by GnRH. The work described in this dissertation addresses the hypothesis that GnRH activates a pathway called the unfolded protein response (UPR) in pituitary gonadotropes and through this pathway exerts specific translational regulation of gonadotrope mRNAs. The work utilizes ribosomal profiling in conjunction with quantitative PCR and bioinformatic analysis in order to examine mRNAs that are sensitive to translational regulation by GnRH and uses pharmacological inhibitors of known GnRH signaling pathways to dissect the pathways contributing to the regulation. Overall the work shows that GnRH activates markers of the UPR, including ER-stress sensor PERK, translation factor eIF2, and transcription factor Xbp1. The work shows that GnRH mobilizes calcium to cause a transient attenuation of translation of Lhb and Cga, the LH subunits. In addition to this, GnRH is shown to regulate the translation of a specific population of other gonadotrope mRNAs, stimulating the translation of some mRNAs while attenuating the translation of others. This specificity is defined by signaling to the UPR as well as the MAPK ERK. This body of work blends the fields of reproductive endocrinology and translational control to provide a novel physiological function for the UPR and establish that GnRH exerts specific and bidirectional regulation of translation.