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

摘要 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，它们最终会在下丘脑中占据位置，控制促性腺激素的释放 脑下垂体。GnRH-1迁移缺陷导致各种类型的低促性腺激素减退症(HH) 以青春期延迟、性腺功能减退和不育为特征的人类。人类体内的HH表现 临床表现为Kallmann综合征(KS)或正常性特发性HH(NIHH)。在KS中，nIHH与 嗅觉上的缺陷。这种联系导致了长期以来流行的观点，即GnRH-1神经元 沿着嗅觉和犁鼻感觉神经元的轴突从鼻子迁移到下丘脑。 然而，我们仍然不知道他关于GnRH-1迁移模式的假设是否属实。 这项应用的总体目标是描绘引导GnRH-1神经元的分子机制 和他们的迁徙脚手架。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，它的发育是通过仅部分重叠的分子信号发生的 与那些控制嗅觉和犁鼻神经发育的人。这一假说的基本原理是 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 诱导GnRH-1神经元错位，不依赖于嗅觉系统的发育。我们的预赛 数据表明，Sonic Hedgehog信号通路的转录激活/抑制因子Gli3控制TN GnRH-1的发育和向大脑的迁移。在我们强劲的初步数据的指引下，我们将测试我们的 通过两个特定的目的进行假说：1)确定转录调节因子Gli3如何调节TN GnRH-1神经元的发育和迁移；2)确定GLI3突变在糖尿病病因中的生物学作用 KS/nIHH在人类中的表达。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和体内外互补实验发现新的 脊椎动物TN发育和功能GnRH-1系统形成的机制。这个 拟议的研究具有重要意义，因为它将推进和扩大KS和NIHH的重要临床信息 人类。这些研究的结果将改进诊断标准，并刺激新技术的发展 改善人类状况的治疗方法和治疗策略。

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.