Regulation of reproduction via tight control of gonadotropin hormone levels
Section snippets
Physiology and pathophysiology of LH and FSH
Gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are synthesized by the anterior pituitary gonadotropes and secreted into the circulation to regulate gonadal function. Every secretory pulse of LH from the pituitary corresponds to a pulse of GnRH from the hypothalamus (Levine et al., 1982). On the other hand, FSH secretion is not entirely regulated by GnRH and most of FSH is constitutively released (Culler and Negro-Vilar, 1987, Levine and Duffy, 1988). In
GnRH receptor signaling pathways that regulate gonadotropin gene expression
The complexity of GnRH signaling provides a variety of regulatory avenues for gonadotropin gene regulation (Fig. 1). Molecular studies that identified signal transduction pathways activated by GnRH receptor (GnRHR) binding have been facilitated with the development of model cells lines. Whole animal studies, although critical for understanding of the HPG axis within the endogenous hormonal setting, can be inconclusive as illustrated above, due to hormonal feedback and the possible effects on
GnRH regulation of LHβ and FSHβ transcription
The specific gonadotropin β subunits are expressed at low basal levels and are differentially induced through pulses of GnRH (Bedecarrats and Kaiser, 2003, Haisenleder et al., 1991, Shupnik, 1996, Weiss et al., 1990). GnRH regulates expression of the specific β subunits through immediate-early genes. Early growth response 1 (EGR1) is an intermediary gene that regulates GnRH induction of LHβ, while activating protein 1 (AP1) transcription factor, comprised of a heterodimer of FOS and JUN
Crosstalk of GnRH with other hormones that regulate gonadotropins
Another possible mechanism of differential regulation is interaction of GnRH signaling pathways and other hormones that regulate gonadotropin levels. Gonadal steroid hormones regulate expression of gonadotropin β subunits and pituitary responsiveness to GnRH, by modulating the levels of induction by GnRH-induced signaling. Pituitary responsiveness to GnRH is regulated by paracrine factors expressed in the pituitary itself.
Conclusion
GnRH differentially regulates gonadotropin β-subunits expression, the limiting components of the mature hormone. Each pulse of GnRH induces a new wave of transcription of immediate early genes, EGR1 that leads to induction of LHβ, and cFOS (and more stable, but less regulated, cJUN) that leads to induction of FSHβ (Fig. 3, Fig. 4). Both EGR1 and cFOS have labile mRNAs and equally unstable proteins, exhibiting rapid turnover and degradation to allow for a tight temporal regulation of gene
Disclosure
The author has nothing to disclose.
Acknowledgements
This work was supported by National Institutes of Health Grant R01 HD057549 to DC.
The author thanks Nancy M. Lainez and Carrie R. Jonak for editorial comments.
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