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

摘要 GnRH-1神经元对脊椎动物的性能力和生育能力是必不可少的。在发育过程中，GnRH-1 神经元从胚胎鼻区迁移到大脑，在那里它们最终定位到 下丘脑控制脑下垂体促性腺激素的释放。GnRH-1迁移过程中的缺陷 引起各种形式的低促性腺激素减退症(HH)，其特点是迟发性 青春期发作、性腺功能减退和不孕不育。人类HH的临床表现为Kallmann综合征 (KS)或正常的特发性HH(NIHH)。在KS中，HH与嗅觉缺陷有关。这 这种联系导致了一种长期流行的观点，即GnRH-1神经元从鼻子迁移到 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)，这是 由不同于嗅觉和犁鼻感觉神经元的神经元组成。 KS和nIHH通常与几种非生殖畸形有关，包括头面部缺陷， 唇腭裂和牙齿发育不全。颅面间充质组织在神经元调控中的关键作用 鼻区的发育和分化。Sonic Hedgehog信号中的调节失调可能导致 各种颅面畸形，包括无前脑畸形、中线缺陷、唇腭裂和牙科 发育不全。Hedgehog下游基因的表达严重依赖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)。通过分析整个外显子组测序 从580名受HH和KS影响的患者的队列数据中，我们确定了候选的罕见Gli3点突变。 我们的中心假设是Gli3的缺失改变了鼻腔释放的诱导信号的表达 间质和脑是终末神经和GnRH-1神经元发育所必需的。我们 提出这一机制是人类KS和NIHH的基础。通过利用老鼠的遗传学，尖端技术 成像，人类全基因组测序，器官培养和现场直接突变实验，我们 将发现诱导因子调节Hedgehog-Gli信号系统控制的新机制 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 为人类KS和NIHH的诊断和设计新的治疗方法提供临床信息。

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.