Amato Enrico, Taroc Ed Zandro M, Forni Paolo E
bioRxiv. 2023 Sep 3:2023.08.31.555770. doi: 10.1101/2023.08.31.555770.
During embryonic development, the olfactory placode (OP) generates migratory neurons, including olfactory pioneer neurons, cells of the terminal nerve (TN), Gonadotropin-releasing hormone-1 (GnRH-1) neurons, and other uncharacterized neurons. Pioneer neurons from the olfactory placode induce olfactory bulb morphogenesis. In mice, GnRH-1 neurons appear in the olfactory system around mid-gestation and migrate via the terminal nerve axons to different brain regions. The GnRH-1 neurons are crucial in controlling the hypothalamic-pituitary-gonadal (HPG) axis. Kallmann syndrome is characterized by impaired olfactory system development, defective olfactory bulbs, defective secretion of GnRH-1, and infertility. The precise mechanistic link between the olfactory system and GnRH-1 development remains unclear. Studies in humans and mice highlight the importance of the Prokineticin-2/Prokineticin-Receptor-2 (Prokr2) signaling pathway in olfactory bulb morphogenesis and GnRH-1 neuronal migration. loss-of-function mutations can cause Kallmann syndrome, and hence the Prokr2 signaling pathway represents a unique model to decipher the olfactory/GnRH-1 connection. We discovered that Prokr2 is expressed in the TN neurons during the critical period of GnRH-1 neuron formation, migration, and induction of olfactory bulb morphogenesis. Single-cell RNA sequencing identified that the TN is formed by neurons that are distinct from the olfactory neurons. The TN neurons express multiple genes associated with KS. Our study suggests that the aberrant development of pioneer/TN neurons might cause the KS spectrum.
在胚胎发育过程中,嗅基板(OP)产生迁移神经元,包括嗅觉先驱神经元、终神经(TN)细胞、促性腺激素释放激素-1(GnRH-1)神经元以及其他未明确特征的神经元。来自嗅基板的先驱神经元诱导嗅球形态发生。在小鼠中,GnRH-1神经元在妊娠中期左右出现在嗅觉系统中,并通过终神经轴突迁移到不同的脑区。GnRH-1神经元在控制下丘脑-垂体-性腺(HPG)轴方面至关重要。卡尔曼综合征的特征是嗅觉系统发育受损、嗅球缺陷、GnRH-1分泌缺陷和不育。嗅觉系统与GnRH-1发育之间的确切机制联系仍不清楚。对人类和小鼠的研究强调了促动力蛋白-2/促动力蛋白受体-2(Prokr2)信号通路在嗅球形态发生和GnRH-1神经元迁移中的重要性。功能丧失突变可导致卡尔曼综合征,因此Prokr2信号通路代表了一个独特的模型来解读嗅觉/GnRH-1联系。我们发现Prokr2在GnRH-1神经元形成、迁移和诱导嗅球形态发生的关键时期在TN神经元中表达。单细胞RNA测序确定TN由与嗅觉神经元不同的神经元组成。TN神经元表达多个与卡尔曼综合征相关的基因。我们的研究表明,先驱/TN神经元的异常发育可能导致卡尔曼综合征谱系。
1)先驱或终神经神经元在启动嗅球发育中起关键作用。我们发现与卡尔曼综合征相关的促动力蛋白受体-2基因由嗅觉先驱/终神经神经元表达。2)我们对啮齿动物的终神经神经元进行了基因追踪、分离和单细胞RNA测序。该分析揭示了与卡尔曼综合征相关的基因表达显著富集。3)我们的研究表明,对先驱/终神经神经元的研究应该是理解影响嗅觉和GnRH-1系统的发育缺陷的关键焦点。