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Robert A. Steiner, Víctor M. Navarro, Tacking Toward Reconciliation on Tacr3/TACR3 Mutations, Endocrinology, Volume 153, Issue 4, 1 April 2012, Pages 1578–1581, https://doi.org/10.1210/en.2012-1032
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Neurons that produce GnRH serve as the final common pathway through which the brain regulates reproduction. Although GnRH neurons have spontaneous secretory activity, afferent input from kisspeptin (Kiss1) neurons is required to drive pulsatile GnRH secretion, initiate the onset of puberty, and regulate normal reproductive function (1–3). Kiss1 neurons in the arcuate nucleus (or infundibular nucleus in primates) coexpress at least two other neuropeptides, neurokinin B (NKB) and dynorphin A (4–6). However, the functional significance of these cotransmitters for reproduction remained a complete mystery until 2009, when it was discovered that patients bearing inactivating mutations in either the TAC3 or TACR3 gene (encoding NKB and its receptor, NK3R, respectively) fail to progress through puberty and exhibit profound hypogonadotropic hypogonadism (7–12). Indeed, this observation echoes the hallmarks seen in humans and mice with disabling mutations or deletions in KISS1R/Kiss1r. Paradoxically, earlier studies in Tacr3−/− mice, which were focused on the neurological functions of NK3R, mentioned anecdotally that mice bearing targeted deletions of the Tacr3 gene appeared to be fertile (13–15). At face value, this finding in mice seemed at odds with the phenotype of patients with TACR3 mutations. So, what's up with this apparent contradiction?
