Negative Feedback Governs Gonadotrope Frequency-Decoding of Gonadotropin Releasing Hormone Pulse-Frequency

Abstract

The synthesis of the gonadotropin subunits is directed by pulsatile gonadotropin-releasing hormone (GnRH) from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common α-subunit, luteinizing hormone β-subunit (LHβ) and follicle-stimulating hormone β-subunit (FSHβ). Three mitogen-activated protein kinases, (MAPKs), ERK1/2, JNK and p38, contribute uniquely and combinatorially to the expression of each of these subunit genes. In this study, using both experimental and computational methods, we found that dual specificity phosphatase regulation of the activity of the three MAPKs through negative feedback is required, and forms the basis for decoding the frequency of pulsatile GnRH. A fourth MAPK, ERK5, was shown also to be activated by GnRH. ERK5 was found to stimulate FSHβ promoter activity and to increase FSHβ mRNA levels, as well as enhancing its preference for low GnRH pulse frequencies. The latter is achieved through boosting the ultrasensitive behavior of FSHβ gene expression by increasing the number of MAPK dependencies, and through modulating the feedforward effects of JNK activation on the GnRH receptor (GnRH-R). Our findings contribute to understanding the role of changing GnRH pulse-frequency in controlling transcription of the pituitary gonadotropins, which comprises a crucial aspect in regulating reproduction. Pulsatile stimuli and oscillating signals are integral to many biological processes, and elucidation of the mechanisms through which the pulsatility is decoded explains how the same stimulant can lead to various outcomes in a single cell.

Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

“…Kanasaki et al initially observed that slow GnRH pulses triggered a more rapid and sustained phosphorylation of ERK1/2 than fast pulses (8). Subsequently, the feedback activity of MKP1, which inactivates MAPK via dephosphorylation, was found to modulate GnRH-induced ERK activation and gonadotropin response to GnRH (34,35). Finally, MKP1 expression was shown to be predominant under high GnRH frequency compared with low GnRH frequency (36).…”

Oscillatory dynamics of the extracellular signal-regulated kinase pathway

“…The intrinsic oscillatory dynamics of the ERK pathway would affect the manner in which it would respond to stimuli from these various sources, especially if they displayed pulsatile or oscillatory behavior as well. For example, the ERK pathway has been shown to respond to pulsatile gonadotrophin-releasing hormone (GnRH) secretion and calcium oscillations and that negative feedback control through ERK is involved in frequency decoding [38,39 ]. It has also been shown through a theoretical analysis that multilevel cascades such as the ERK pathway can act as band-pass filters that respond optimally to calcium signals of a particular frequency [40,41].…”

Pin1 Facilitates the Phosphorylation-Dependent Ubiquitination of SF-1 To Regulate Gonadotropin β-Subunit Gene Transcription

“…GnRH-induced signaling to the gonadotropin genes is predominantly via the PKC pathway and downstream MAPK cascades, including extracellular signal-related kinase 1/2 (ERK1/ 2), Jun N-terminal kinase (JNK), p38 MAPK, and big MAPK (BMK or ERK5), while PKA is also activated following GnRH-induced increases in cyclic AMP (29,42). Many of the transcription factors that regulate expression of the gonado- tropin genes are activated through phosphorylation by these kinases and thus contain pSer/Thr-Pro motifs.…”