Camera Mattia, Russo Isabella, Zamboni Valentina, Ammoni Alessandra, Rando Simona, Morellato Alessandro, Cimino Irene, Angelini Costanza, Giacobini Paolo, Oleari Roberto, Amoruso Federica, Cariboni Anna, Franceschini Isabelle, Turco Emilia, Defilippi Paola, Merlo Giorgio R
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, Inserm U1172, Lille, France.
Front Neurosci. 2022 Feb 14;16:744693. doi: 10.3389/fnins.2022.744693. eCollection 2022.
p140Cap, encoded by the gene (, is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in KO mice appeared normal, and young KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.
由基因（此处原文基因名称缺失）编码的p140Cap是一种衔接子/支架蛋白，在小鼠大脑中高度表达，参与多种突触前和突触后机制。基因敲除（KO）雌性小鼠表现出严重的生育力低下、青春期开始延迟、发情周期改变、排卵减少以及动情前期促黄体生成素和雌二醇分泌缺陷。我们研究了p140Cap在下丘脑促性腺系统发育和成熟中的作用。在胚胎发育过程中，KO小鼠中促性腺激素释放激素（GnRH）神经元从鼻基板迁移到前脑的过程似乎正常，年轻的KO动物显示出正常数量的GnRH免疫反应性（-ir）神经元。相比之下，成年KO小鼠显示出GnRH-ir神经元显著减少，以及正中隆起中GnRH-ir投射密度降低，同时下丘脑和垂体中GnRH和LH mRNA水平分别降低。我们检查了第三脑室室周前部区域的 kisspeptin（KP）神经元数量、弓状核中KP-ir纤维数量以及GnRH神经元上的KP-ir 点状结构数量，但未发现显著变化。一致地，对外源性KP的反应性未改变，排除了在KP受体或其信号转导水平上GnRH神经元的细胞自主缺陷。由于下丘脑的谷氨酸能信号传导对于青春期开始和GnRH分泌的调节都至关重要，我们检查了KO小鼠中谷氨酸能突触的密度，观察到视前区和GnRH神经元上VGLUT-ir点状结构的密度均显著降低。我们的数据表明，在缺乏p140Cap的情况下，下丘脑的谷氨酸能神经回路发生改变，并且这是雌性生育所必需的。
