Role of inductive signals released by nasal mesenchyme and brain in controlling terminal nerve development and GnRH-1 neuronal migration

鼻间充质和大脑释放的诱导信号在控制终末神经发育和 GnRH-1 神经元迁移中的作用

• 批准号: 9590917
• 负责人: Paolo E Forni
• 金额: $ 44.99万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9590917
• 关键词: Affect; Afferent Neurons; Area; Axon; Bioinformatics; Biological; Biological Assay; Biological Testing; Brain; Cell Line; Cleft Lip; Cleft Palate; Clinical; Collaborations; Competence; Confocal Microscopy; Craniofacial Abnormalities; DNA; Data; Defect; Dental; Development; Diagnosis; Diagnostic; Embryo; Embryonic Development; Endocrine; Erinaceidae; Family; Fertility; GLI3 gene; GNRH1 gene; Gene Expression; General Hospitals; Genes; Genetic; Glioblastoma; Holoprosencephaly; Human; Human Genome; Hypogonadism; Hypothalamic structure; Image; Impairment; In Situ Hybridization; In Vitro; Infertility; Kallmann Syndrome; Klinefelter' s Syndrome; Ligands; Light; Luciferases; Mammals; Massachusetts; Mesenchymal; Mesenchyme; Mission; Modeling; Mus; Mutant Strains Mice; Mutate; Mutation; Nerve; Neuronal Differentiation; Neurons; Nose; Pathogenicity; Patients; Pituitary Gland; Pituitary Gonadotropins; Play; Point Mutation; Proteins; Public Health; Reporter; Research; Role; Route; SHH gene; Sampling; Series; Sexual Maturation; Signal Induction; Signal Transduction; Site-Directed Mutagenesis; Smell Perception; System; Tissues; Transcriptional Regulation; United States National Institutes of Health; Variant; Vertebrates; associated symptom; cell motility; cleft lip and palate; cohort; comparative; craniofacial; craniofacial complex; craniofacial development; design; exome sequencing; experimental study; gene product; genome sequencing; human data; loss of function mutation; migration; mutant; negative affect; neurogenesis; neuron development; novel therapeutic intervention; reproductive; smoothened signaling pathway; transcription factor; transcriptome

Summary GnRH-1 neurons are essential for sexual competence and fertility in vertebrates. During development, GnRH-1 neurons migrate from the embryonic nasal area into the brain, where they eventually localize to the hypothalamus to control the release of gonadotropins from the pituitary gland. Defects in GnRH-1 migration cause various forms of hypogonadotropic hypogonadism (HH) in humans, which is 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, HH 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, our recent data suggest that the migration of the GnRH-1 neurons to the hypothalamus may rely on the terminal nerve (TN), which is formed by neurons distinct from the olfactory and vomeronasal sensory neurons. KS and nIHH are often associated with several non-reproductive anomalies including craniofacial defects, cleft/lip palate and dental agenesis. Craniofacial mesenchymal tissues play a pivotal role in controlling neuronal development and differentiation in the nasal area. Dysregulations in Sonic Hedgehog signaling can cause various craniofacial abnormalities, including holoprosencephaly, midline defects, cleft lip/palate and dental agenesis. Expression of genes downstream of hedgehog critically depend on interactions with the glioblastoma gene products (Gli) family of transcription factors (Gli1, Gli2, and Gli3). By analyzing whole exome sequencing data from a cohort of 580 patients affected by HH and KS, we identified candidate rare Gli3 point mutations. Our central hypothesis is that loss of Gli3 alters the expression of inductive signals, released by nasal mesenchyme and brain, which are necessary for terminal nerve and GnRH-1 neuronal development. We propose that this mechanism underlies KS and nIHH in humans. By exploiting mouse genetics, cutting edge imaging, human whole genome sequencing, organotypic cultures and site direct mutagenesis experiments, we will discover new mechanisms by which inductive factors modulate the hedgehog-Gli signaling system to control formation of a functional GnRH-1 system in vertebrates. Successful completion of our study will generate crucial clinical information for diagnostics and designing novel therapeutic approaches for KS and nIHH in humans.

概括 GnRH-1 神经元对于脊椎动物的性能力和生育能力至关重要。在发育过程中，GnRH-1 神经元从胚胎鼻区迁移到大脑，最终定位到 下丘脑控制垂体释放促性腺激素。 GnRH-1 迁移缺陷 导致人类各种形式的低促性腺激素性性腺功能减退症 (HH)，其特征是迟发性 青春期开始、性腺机能减退和不育。人类 HH 临床表现为卡尔曼综合征 (KS) 或正常特发性 HH (nIHH)。在 KS 中，HH 与嗅觉缺陷有关。这 这种关联导致人们长期以来普遍认为 GnRH-1 神经元从鼻子迁移到鼻子 下丘脑沿着嗅觉和犁鼻感觉神经元的轴突。然而，我们最近的数据表明 GnRH-1神经元向下丘脑的迁移可能依赖于终末神经（TN），即 由不同于嗅觉和犁鼻感觉神经元的神经元形成。 KS 和 nIHH 通常与多种非生殖异常相关，包括颅面缺陷、 腭裂/唇腭裂和牙齿发育不全。颅面间充质组织在控制神经元中发挥着关键作用 鼻区的发育和分化。 Sonic Hedgehog 信号传导失调可能会导致 各种颅面异常，包括前脑无裂畸形、中线缺陷、唇裂/腭裂和牙齿 发育不全。刺猬下游基因的表达关键取决于与胶质母细胞瘤的相互作用 基因产物 (Gli) 转录因子家族（Gli1、Gli2 和 Gli3）。通过分析全外显子组测序 根据来自 580 名受 HH 和 KS 影响的患者的队列数据，我们确定了候选的罕见 Gli3 点突变。 我们的中心假设是，Gli3 的缺失会改变鼻腔释放的诱导信号的表达。 间充质和大脑，是终末神经和 GnRH-1 神经元发育所必需的。我们 认为该机制是人类 KS 和 nIHH 的基础。通过利用小鼠遗传学，尖端技术 成像、人类全基因组测序、器官型培养和定点突变实验，我们 将发现诱导因子调节hedgehog-Gli信号系统以控制的新机制 脊椎动物中功能性 GnRH-1 系统的形成。成功完成我们的研究将产生至关重要的 用于人类 KS 和 nIHH 诊断和设计新治疗方法的临床信息。