Deciphering the functional role of MKRN3 in puberty and reproduction

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The hypothalamic-pituitary-gonadal (HPG) axis regulates puberty initiation and reproductive function. The timing of puberty initiation is associated with risks for development of a wide range of diseases in adulthood, including obesity, diabetes, cardiovascular/cardiometabolic disorders, and cancer. Pubertal development is a complex process that is regulated by the activity of the HPG axis and is influenced by genetic, nutritional and environmental factors. The HPG axis is active in the embryonic and neonatal stages of life; it is then suppressed during childhood until reactivation at the time of puberty. Premature re-activation of the HPG axis results in central precocious puberty (CPP). The precise mechanisms that regulate GnRH secretion to constrain the HPG axis during infancy and childhood and subsequently trigger puberty initiation remain elusive. Genetic studies of patients with reproductive disorders have led to identification of genes that regulate GnRH secretion and have increased our understanding of the neuroendocrine regulation of reproductive function. We used an unbiased approach to identify loss-of-function mutations in MKRN3 in patients with CPP, linking this imprinted gene with the reproductive axis for the first time. Mutations in MKRN3 are now recognized to be the most common genetic cause of CPP. The long-term goal of this project is to elucidate the molecular, cellular, and physiologic mechanisms by which MKRN3 controls the timing of puberty onset. We hypothesize that MKRN3 acts in the hypothalamus to inhibit the reproductive axis. In the first aim of this proposal, we will study the roles and mechanisms of action of MKRN3 in male and female neural development and synaptic plasticity during puberty. In the second aim, we will examine candidate targets of MKRN3, including KISS1, NKB, IGF2BP1 and LIN28B, as well as mRNA targets, in the regulation of the reproductive axis. In the third aim, we will identify new MKRN3 targets and leverage mutations in key protein domains identified in patients with CPP to investigate the roles of different MKRN3 domains in protein function. The successful completion of these aims will help us to understand the actions of MKRN3, a novel regulator of GnRH re-activation, in the neuroendocrine control of pubertal timing. A better understanding of the role of MRKN3 may also identify novel factors involved in the neuroendocrine control of reproduction and lead to the development of new tools for the management of pubertal and reproductive disorders.