Gonadotropin-releasing hormone: gene evolution, expression, and regulation

The gonadotropin-releasing hormone (GnRH) gene is a superb example of the diverse regulation that is required to maintain the function of an evolutionarily conserved and fundamental gene. Because reproductive capacity is critical to the survival of the species, physiological homeostasis dictates optimal conditions for reproductive success, and any perturbation from this balance may affect GnRH expression. These disturbances may include alterations in signals dictated by stress, nutritional imbalance, body weight, and neurological problems; therefore, changes in other neuroendocrine systems may directly influence the hypothalamic-pituitary-gonadal axis through direct regulation of GnRH. Thus, to maintain optimal reproductive capacity, the regulation of the GnRH gene is tightly constrained by a number of diverse signaling pathways and neuromodulators. In this review, we summarize what is currently known of GnRH gene structure, the location and function of the two isoforms of the GnRH gene, some of the many hormones and neuromodulators found to affect GnRH expression, and the molecular mechanisms responsible for the regulation of the GnRH gene. We also discuss the latest models used to study the transcriptional regulation of the GnRH gene, from cell models to evolving in vivo technologies. Although we have come a long way in the last two decades toward uncovering the intricacies behind the control of the GnRH neuron, there remain vast distances to cover before direct therapeutic manipulation of the GnRH gene to control reproductive competence is possible.