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

了解转录因子 Gli3 在卡尔曼综合征和正常形式的特发性低促性腺激素性性腺功能减退症中的作用。

• 批准号: 9892022
• 负责人: Paolo E Forni
• 金额: $ 23.43万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892022
• 关键词: Ablation; Address; Affect; Afferent Neurons; Animals; Area; Axon; Biological; Brain; Candidate Disease Gene; Cells; Clinical; Competence; Complex; Cues; DNA Sequence Alteration; Data; Defect; Destinations; Development; Diagnosis; Diagnostic; Embryo; Embryonic Development; Etiology; Fertility; Foundations; GLI3 gene; GNRH1 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Human; Human Genetics; Human Genome; Hypogonadism; Hypothalamic structure; Idiopathic Hypogonadotropic Hypogonadism; Imaging Techniques; Impairment; In Situ Hybridization; In Vitro; Infertility; Kallmann Syndrome; Klinefelter' s Syndrome; Knockout Mice; Link; Mammals; Mesenchyme; Mission; Molecular; Molecular Diagnosis; Mus; Mutant Strains Mice; Mutate; Mutation; Nature; Nerve; Neurons; Nose; Olfactory Pathways; Outcome; Pathogenicity; Pattern; Pituitary Gland; Pituitary Gonadotropins; Positioning Attribute; Public Health; Reporter; Research; Role; Route; SHH gene; Signal Induction; Signal Transduction; Smell Perception; Stratification; System; Systems Development; Testing; Therapeutic; Three-Dimensional Imaging; Transcription Coactivator; United States National Institutes of Health; Variant; Vertebrates; causal variant; exome sequencing; experimental study; genetic architecture; genetic pedigree; genome sequencing; improved; in vitro testing; in vivo; innovation; loss of function; loss of function mutation; migration; mind control; mouse genetics; mutant; negative affect; neuron development; novel; novel therapeutics; olfactory bulb; personalized diagnostics; personalized medicine; scaffold; smoothened signaling pathway; transcription factor; transcriptome; treatment strategy

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.

概括 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， 它们最终将在下丘脑中占据一席之地，以控制促性腺激素的释放 垂体。 GnRH-1 迁移缺陷会导致多种类型的低促性腺激素性性腺功能减退症 (HH) 人类，其特点是青春期延迟、性腺功能减退和不育。 HH 在人类中的表现 临床上为卡尔曼综合征 (KS) 或正常特发性 HH (nIHH)。在 KS 中，nIHH 与 嗅觉缺陷。这种关联导致人们长期以来普遍认为 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，我们仍然不知道他对 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 和他们的迁徙脚手架。我们的中心假设指出 GnRH-1 神经元迁移到下丘脑 位于终末神经 (TN) 上，其发育是通过仅部分重叠的分子信号进行的 与控制嗅觉和犁鼻神经元发育的神经元有关。该假设的基本原理源自 了解与 KS 和 nIHH 相关的特定基因突变如何对 TN 发展产生负面影响 并诱导 GnRH-1 神经元错位，独立于嗅觉系统的发育。我们的初步 数据表明，音刺猬信号通路的转录激活子/阻遏子 Gli3 控制 TN 发育和 GnRH-1 迁移到大脑。在我们强大的初步数据的指导下，我们将测试我们的 通过两个具体目标提出假设：1）确定转录调节因子 Gli3 如何调节 TN 发育和 GnRH-1 神经元迁移以及 2) 定义 GLI3 突变在病因学中的生物学作用 人类中的 KS/nIHH。我们的方法是创新的。我们将利用小鼠遗传学、先进的成像技术、 人类全基因组测序数据和互补的体外和体内实验以发现新的 脊椎动物中 TN 发育和功能性 GnRH-1 系统形成的机制。这 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并刺激新型药物的开发 改善人类状况的治疗和治疗策略。