Deciphering the functional role of MKRN3 in puberty and reproduction

下丘脑-垂体-性腺（HPG）轴调节青春期启动和生殖功能。定时 青春期的开始与成年期发生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。青春期的发展是一个复杂的 这一过程是由HPG轴的活动调节，并受到遗传，营养和 环境因素HPG轴在生命的胚胎和新生儿阶段是活跃的;然后被抑制 直到青春期时重新激活。HPG轴的过早重新激活导致 中枢性性早熟（CPP）。调节GnRH分泌以限制HPG的精确机制 轴在婴儿期和儿童期以及随后触发青春期启动仍然难以捉摸。的遗传学研究 患有生殖障碍的患者已经鉴定出调节GnRH分泌的基因， 增加了我们对生殖功能的神经内分泌调节的理解。我们使用了一个无偏的 一种鉴定CPP患者MKRN 3功能缺失突变的方法，将该印迹基因与 生殖轴的第一次。MKRN 3的突变现在被认为是最常见的遗传病。 因为CPP。该项目的长期目标是阐明分子，细胞和生理 MKRN 3控制青春期开始时间的机制。我们假设MKRN 3在 下丘脑抑制生殖轴。在本提案的第一个目标中，我们将研究 MKRN 3在青春期的雄性和雌性神经发育和突触可塑性中的作用机制。 在第二个目标中，我们将检查MKRN 3的候选靶标，包括KISS 1，NKB，IGF 2BP 1和LIN 28 B， 以及mRNA的目标，在调节生殖轴。在第三个目标中，我们将确定新的MKRN 3 靶点，并利用CPP患者中鉴定的关键蛋白质结构域中的突变， 不同的MKRN 3结构域的蛋白质功能。这些目标的成功实现将有助于我们了解 MKRN 3是一种新的GnRH再激活调节剂，在青春期时间的神经内分泌控制中起作用。 更好地理解MRKN 3的作用也可能发现参与神经内分泌调节的新因子。 控制生殖，并导致开发新的工具来管理青春期， 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.