Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
Department of Health Sciences, University of Milan, Via di Rudinì 8, 20142, Milano, Italy.
Nat Commun. 2023 Dec 7;14(1):8097. doi: 10.1038/s41467-023-43820-z.
Innervation of the hypothalamic median eminence by Gonadotropin-Releasing Hormone (GnRH) neurons is vital to ensure puberty onset and successful reproduction. However, the molecular and cellular mechanisms underlying median eminence development and pubertal timing are incompletely understood. Here we show that Semaphorin-6A is strongly expressed by median eminence-resident oligodendrocytes positioned adjacent to GnRH neuron projections and fenestrated capillaries, and that Semaphorin-6A is required for GnRH neuron innervation and puberty onset. In vitro and in vivo experiments reveal an unexpected function for Semaphorin-6A, via its receptor Plexin-A2, in the control of median eminence vascular permeability to maintain neuroendocrine homeostasis. To support the significance of these findings in humans, we identify patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset.
促性腺激素释放激素 (GnRH) 神经元对下丘脑正中隆起的神经支配对于确保青春期开始和成功繁殖至关重要。然而，正中隆起发育和青春期开始的分子和细胞机制尚不完全清楚。在这里，我们表明，神经丝蛋白-6A 在位于 GnRH 神经元投射和有孔毛细血管附近的正中隆起常驻少突胶质细胞中强烈表达，并且神经丝蛋白-6A 是 GnRH 神经元神经支配和青春期开始所必需的。体外和体内实验揭示了神经丝蛋白-6A 通过其受体 Plexin-A2 具有控制正中隆起血管通透性以维持神经内分泌平衡的意外功能。为了支持这些发现对人类的重要性，我们鉴定了患有青春期延迟的患者，他们携带 SEMA6A 的一种新的致病性变异。总之，我们的数据揭示了神经丝蛋白-6A 通过调节正中隆起血管屏障来调节 GnRH 神经元模式形成，从而控制青春期开始的作用。
