ELAVL1 Elevates Insights: The Ups and Downs of Regulated mRNA Translation in the Control of Gonadotropin Release

Gonadotropes are a dynamic subset of cells in the anterior pituitary in that they are transcriptionally and translationally remodeled every cycle to support a well-timed preovulatory LH surge and a broader, secondary surge in FSH (1). The hypothalamus secretes GnRH, which binds to gonadotropes and provides a critical signal for driving the basal-level and surge-level (in the case of LH) production and secretion of gonadotropins. The gonadotrope is able to distinguish variations in GnRH pulse frequencies to the extent that LH and FSH will be preferentially produced and/or secreted after distinct GnRH pulse patterns. Therefore, the production of the GnRH receptor (GnRHR) by gonadotropes is a critical process for reproductive success.

In rodents, transcription of critical gonadotrope mRNAs [Lhb, Fshb, and GnRHRs (Gnrhr)] is tightly regulated throughout the estrous cycle, fluctuating appropriately to accommodate increasing protein synthesis in preparation for ovulation. Estradiol from developing follicles and increasing pulses of GnRH promote active translation of LH, FSH, and GnRHR to ensure maximal expression in diestrus or proestrus. During this period, the gonadotropes become remodeled, extending processes to blood vessels with sufficient surface GnRHRs to receive the GnRH stimulation (2). Because of the importance of increasing GnRHR expression on the ability of the gonadotrope to synthesize and secrete surge level gonadotropins, the translation of Gnrhr mRNA early in the cycle constitutes an important gateway to successful reproduction (1).

Recent evidence has suggested that posttranscriptional control of gonadotrope function might be an important regulatory mechanism underlying the cyclic accumulation of GnRHRs and gonadotropins. Using preexisting mRNA templates, this regulatory strategy enables a rapid response to physiological cues mediated through RNA binding proteins that control the translation and/or stability of targeted mRNAs. In a recent example, it was shown that the cell fate determinant, Musashi, can bind specifically to the Gnrhr mRNA 3′ untranslated region (UTR) and exert translational repression (3). Leptin signaling was proposed to inhibit Musashi function to allow for GnRHR protein accumulation, gonadotropin release, and reproductive competence in female mice.

As described recently by Terasaka et al. (4), the Lawson group have separately demonstrated a substantial contribution of regulated mRNA translation in the murine LβT2 gonadotrope cell line in response to GnRH. The investigators hypothesized that altered mRNA stability could underlie some of the GnRH-induced mRNA translational changes. Terasaka et al. (4) reported that multiple gonadotrope mRNAs, including the Gnrhr mRNA, are controlled via the adenylate-uridylate rich element (ARE) binding protein, embryonic lethal, abnormal vision-like 1 (ELAVL1, also known as human antigen R) to enhance target mRNA stability and translation.

ARE motifs located in the 3′ UTR modulate the stability of target mRNAs. The stabilization or destabilization of the ARE-containing mRNAs is dictated by a number of ARE binding proteins, which differ in their ability to either reduce or enhance stability through recruitment of specific regulatory cofactors (5). The ELAVL1 protein has generally been implicated in promoting target mRNA stability to enhance translation (6), and its activity must be tightly controlled because dysregulation has been implicated in a number of human diseases, including inflammation and cancer (7).

Terasaka et al. (4) identified multiple, diverse mRNAs that interact specifically with ELAVL1 in the murine LβT2 gonadotrope cell line, suggesting that ELAVL1 exerts broad and coordinated control on the gonadotrope proteome. One of the identified ELAVL1 targets was the Gnrhr mRNA. Knockdown of ELAVL1 in LβT2 resulted in reduced Gnrhr mRNA levels, reduced cell surface expression of GnRHR, and reduced LH secretion in response to GnRH. They reported that the effect on LH levels was likely indirect, because ELAVL1 did not interact with the Lhb mRNA. GnRH pulses transiently induced an unfolded protein response and paused general mRNA translation. Terasaka et al. suggested that an association with ELAVL1 might allow target mRNAs to bypass this GnRH-induced translational pausing. Together, these observations argue that ELAVL1 plays a critical role in regulating pituitary gonadotropes to optimize gonadotropin release in response to GnRH signals, although future in vivo studies are required to corroborate this conclusion.

A small subset of the identified ELAVL1 target mRNAs showed enhanced binding after GnRH stimulation. The functional distinction between the two classes of ELAVL1 target mRNAs, those constitutively associated and those GnRH recruited, is not clear. One possibility is that the newly recruited mRNAs might be critical to decode the frequency of the GnRH pulses to entrain the subsequent LH surge. It will be very interesting to determine how ELAVL1 differentially binds and modulates the stability of these two target mRNA classes.

GnRH stimulation was also shown to mediate translocation of some ELAVL1 to the nucleus, where it was eventually degraded. The reason for nuclear targeting is unclear, because the overall levels of ELAVL1 did not alter significantly after GnRH stimulation. Recent studies have suggested that ELAVL1 might bind to a range of newly synthesized pre-mRNAs containing intronic AREs (8). Because introns can enhance mRNA translation by promoting polyadenylation and mRNA export without necessarily affecting stability (9), it would be informative to analyze the translation of newly synthesized gonadotrope mRNAs with intronic AREs after GnRH stimulation.

It is now clear that both ELAVL1 and Musashi can exert translational control of the Gnrhr mRNA. It will be interesting to determine whether Musashi and ELAVL1 act independently, cooperatively, or exert opposing regulatory inputs on Gnrhr mRNA translation. Musashi and ELAVL1 have been identified within common mRNA ribonucleoprotein complexes (10, 11). An in silico analysis predicts that Musashi1 can bind to the 3′ UTR of both human ELAVL1 (NM_001419) and mouse Elavl1 (NM_010485) mRNAs. These observations suggest that the regulation of ELAVL1 and Musashi activity and/or translation of their respective mRNAs might be interdependent.

Given the need for tight control of gonadotropin hormone release, it is perhaps not too surprising that multiple mRNA translational control pathways could be involved to fine tune gonadotrope functionality. This ground-breaking study by Terasaka et al. (4) has highlighted the increasing importance of posttranscriptional regulatory mechanisms in the control of reproduction.

Glossary

Abbreviations:

ARE

adenylate-uridylate rich element

ELAVL1

embryonic lethal, abnormal vision-like 1

GnRH

GnRH receptor

UTR

untranslated region

Additional Information

Disclosure Summary: The authors have nothing to disclose.

Data Availability:

All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.