Deciphering the functional role of MKRN3 in puberty and reproduction

下丘脑-垂体-性腺(HPG)轴调节青春期的启动和生殖功能。时间的选择 青春期启动与成年后罹患多种疾病的风险有关，包括 肥胖、糖尿病、心血管/心脏代谢紊乱和癌症。青春期发育是一个复杂的过程。 受HPG轴活动调节并受遗传、营养和营养因素影响的过程 环境因素。HPG轴在生命的胚胎和新生儿阶段是活跃的；然后它被抑制 在童年期间，直到青春期时重新激活。HPG轴过早重新激活会导致 中枢性性早熟(CPP)。调节GnRH分泌以抑制HPG的精确机制 在婴儿期和儿童期并随后触发青春期启动的中枢神经系统仍然难以捉摸。遗传病的研究 患有生殖障碍的患者已经发现了调节GnRH分泌的基因，并 增加了我们对生殖功能的神经内分泌调节的理解。我们使用了不偏不倚的 一种鉴定CPP患者MKRN3功能缺失突变的方法，将该印记基因与 第一次发现了生殖轴。MKRN3的突变现在被认为是最常见的基因 CPP的原因。这个项目的长期目标是阐明分子、细胞和生理学。 MKRN3控制青春期开始时间的机制。我们假设MKRN3在 下丘脑抑制生殖轴。在这项建议的第一个目标中，我们将研究 MKRN3在青春期男女神经发育和突触可塑性中的作用机制。 在第二个目标中，我们将研究MKRN3的候选靶点，包括KISS1、NKB、IGF2BP1和Lin28b， 以及mRNA靶标，在生殖轴的调节中。在第三个目标中，我们将确定新的MKRN3 靶点和利用在CPP患者中发现的关键蛋白结构域的突变来研究 不同的MKRN3结构域在蛋白质功能上的差异。这些目标的成功实现将有助于我们理解 MKRN3，一种新的GnRH重新激活的调节器，在神经内分泌控制青春期时机中的作用。 更好地了解MRKN3的作用也可能确定与神经内分泌有关的新因素 控制生殖并导致开发新的青春期和青春期管理工具 生殖障碍。

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.