Post-Transcriptional Regulation of Gnrhr: A Checkpoint for Metabolic Control of Female Reproduction

Abstract

The proper expression of gonadotropin-releasing hormone receptors (GnRHRs) by pituitary gonadotropes is critical for maintaining maximum reproductive capacity. GnRH receptor expression must be tightly regulated in order to maintain the normal pattern of expression through the estrous cycle in rodents, which is believed to be important for interpreting the finely tuned pulses of GnRH from the hypothalamus. Much work has shown that Gnrhr expression is heavily regulated at the level of transcription. However, researchers have also discovered that Gnrhr is regulated post-transcriptionally. This review will discuss how RNA-binding proteins and microRNAs may play critical roles in the regulation of GnRHR expression. We will also discuss how these post-transcriptional regulators may themselves be affected by metabolic cues, specifically with regards to the adipokine leptin. All together, we present evidence that Gnrhr is regulated post-transcriptionally, and that this concept must be further explored in order to fully understand the complex nature of this receptor.

Leptin: A Metabolic Signal for the Differentiation of Pituitary Cells

“…[5]). GnRH and estradiol both stimulate Gnrhr mRNA during this time (reviewed in [9]). Leptin's role is to de-repress Musashi's actions on Gnrhr Gonadotropes are remodeled early in the cycle by estrogens, GnRH, and leptin to support the ovary.…”

“…Thus, our studies show that, whereas leptin does not regulate Gnrhr mRNA directly, it works in partnership with estradiol and GnRH to permit its translation by regulating MSI. This is another checkpoint in reproductive cycles [7,9]. Reduced leptin, due to fasting for example, may signal poor nutrition and thus reduce translation of GnRHR [7][8][9] and GnRH binding sites [23].…”

“…This is another checkpoint in reproductive cycles [7,9]. Reduced leptin, due to fasting for example, may signal poor nutrition and thus reduce translation of GnRHR [7][8][9] and GnRH binding sites [23]. Ultimately, leptin reduction of ablation slows or prevents reproduction.…”

“…Leptin is one of the most important of these extrinsic signals. However, recent studies show that leptin does more than simply signal levels of fat stores [1][2][3][4][5][6][7][8][9][10][11]. Leptin plays a trophic role that optimizes and maintains differentiation of at least two of these cell types, somatotropes and gonadotropes.…”

Mechanisms Driving Palmitate-Mediated Neuronal Dysregulation in the Hypothalamus

“…Prior to the onset of puberty, these miRNAs are increased, leading to the downregulation of the targeted GnRH repressors, and ultimately lead to increased GnRH [177]. In addition, 16 other miRNAs have been identified by in silico analysis to directly target the 3 UTR of GnRH but none have been experimentally validated [178]. Another miRNA that has been associated with the onset of puberty in the hypothalamus is miR-30b.…”