Understanding the role of the transcription factor Gli3 in Kallmann syndrome and normosmic forms of idiopathic hypogonadotropic hypogonadism.

总结 GnRH-1神经元是大脑中控制青春期开始、性能力和生育能力的细胞， 脊椎动物在发育过程中，GnRH-1神经元从胚胎鼻区迁移到大脑， 在那里，它们最终会占据下丘脑的位置，以控制促性腺激素的释放。 脑下垂体GnRH-1迁移缺陷可诱导各种类型的低促性腺激素性性腺功能减退症（HH）， 人类，特征为青春期延迟、性腺功能减退和不育。人类HH表现 临床上称为卡尔曼综合征（KS）或正常嗅觉特发性HH（nIHH）。在KS中，nIHH与 嗅觉上的缺陷。这种关联导致了长期以来的流行观点，即GnRH-1神经元 从鼻沿着嗅觉和犁鼻感觉神经元的轴突迁移到下丘脑。 然而，我们仍然不知道他关于GnRH-1迁移模式的假设是否正确。 本申请的总体目标是描述引导GnRH-1神经元的分子机制 和它们的迁徙脚手架我们的中心假设是GnRH-1神经元迁移到下丘脑 在终末神经（TN）上，其发育通过仅部分重叠的分子信号发生 控制嗅觉和犁鼻神经元发育的神经元。这一假设的基本原理来自于 从了解与KS和nIHH相关的特定基因突变如何对TN的发展产生负面影响 并诱导GnRH-1神经元错位，与嗅觉系统发育无关。我们的初步 数据表明，音刺猬信号通路的转录激活子/抑制子Gli 3控制TN 促性腺激素释放激素-1向大脑迁移。在我们强大的初步数据的指导下，我们将测试我们的 通过两个特定的目标假设：1）确定转录调节因子Gli 3如何调节TN 发育和GnRH-1神经元迁移和2）定义GLI 3突变在神经元迁移的病因学中的生物学作用。 人类KS/nIHH。我们的方法是创新的。我们将利用老鼠遗传学，先进的成像技术， 人类全基因组测序数据以及互补的体外和体内实验来发现新的 TN的发展和功能性GnRH-1系统在脊椎动物形成的机制。的 拟议的研究意义重大，因为它将推进和扩展KS和nIHH的重要临床信息， 人类这些研究的结果将改善诊断标准，促进新的 治疗和治疗策略，以改善人类状况。

Summary The GnRH-1 neurons are cells in the brain that control pubertal onset, sexual competence and fertility of vertebrates. During development, the GnRH-1 neurons migrate from the embryonic nasal area into the brain, where they will eventually take up positions in the hypothalamus to control the release of gonadotropins from the pituitary gland. Defects in GnRH-1 migration induce various types of hypogonadotropic hypogonadism (HH) in humans, characterized by delayed pubertal onset, hypogonadism, and infertility. HH in humans manifests clinically as either Kallmann syndrome (KS) or normosmic idiopathic HH (nIHH). In KS, nIHH is associated with deficiencies in the sense of smell. This association led to the long-held, prevailing view that the GnRH-1 neurons migrate from the nose to the hypothalamus along the axons of olfactory and vomeronasal sensory neurons. However, we still do not know whether his assumption of GnRH-1 migration patterns is true. The overall objective of this application is to delineate the molecular mechanisms that guide GnRH-1 neurons and their migratory scaffold. Our central hypothesis states that GnRH-1 neurons migrate to the hypothalamus on the Terminal Nerve (TN), whose development occurs through molecular signals that only partially overlap with those controlling olfactory and vomeronasal neuronal development. The rationale for this hypothesis derives from understanding how specific genetic mutations linked to KS and nIHH can negatively affect TN development and induce GnRH-1 neuron mispositioning, independent from the olfactory system development. Our preliminary data indicate that transcriptional activator/repressor of the sonic hedgehog signaling pathway, Gli3, controls TN developments and GnRH-1 migration to the brain. Guided by our strong preliminary data, we will test our hypothesis through two specific aims: 1) Determine how the transcriptional regulator Gli3 regulates TN development and GnRH-1 neuronal migration and 2) Define the biologic role of GLI3 mutations in the etiology of KS/nIHH in humans. Our approach is innovative. We will exploit mouse genetics, advanced imaging techniques, human whole genome sequencing data and complementary in-vitro and in-vivo experiments to discover new mechanisms underlying TN development and formation of a functional GnRH-1 system in vertebrates. The proposed research is significant, since it will advance and expand vital clinical information for KS and nIHH in humans. The results from these studies will improve diagnostic criteria and stimulate the development of novel treatments and therapeutic strategies to improve the human condition.