Rites of passage through puberty: A complex genetic ensemble

Abstract

Worldwide, puberty is recognized by various cultures and celebrated as a rite of passage into adulthood. The methodical drumbeat of these religious and social ceremonies foreshadows the rhythm of reproduction that, in many ways, marks the final stage of development. Despite its social and physiological significance, including perpetuation of the species, the pathways that regulate the onset of puberty have evaded traditional physiological inquiries. No clear hormonal or metabolic trigger has been identified as a switch that activates the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator (1). Instead, geneticabnormalities that preclude puberty have provided the major insights into the pathways that are critical for the development and maturation of the reproductive axis (2, 3). Perhaps the best candidate for regulating the onset of puberty is kisspeptin, the ligand for the receptor encoded by GPR54, a gene identified as a cause of recessive hypogonadotropic hypogonadism (4, 5). The report by Pitteloud et al. (6) in this issue of PNAS identifies loss-of-function mutations in the prokineticin 2 (PROK2) gene, which encodes a secreted peptide that regulates the development and migration of the olfactory tract and GnRH neuron progenitors. The PROK2 mutations caused hypogonadotropic hypogonadism in both males and females. Using Prok2 −/− knockout mice, the GnRH neuron progenitors were shown to cross the cribriform plate but fail to migrate into and populate the hypothalamus. Interestingly, olfactory tract development in humans with PROK2 mutations was variable, resulting in both nonanosmic and anosmic forms of hypogonadotropic hypogonadism. This report highlights the role of genetics as a means to unravel complex developmental processes and helps explain why anosmia is a frequent, but variable, feature of inherited forms of hypogonadotropic hypogonadism.