Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.
Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.
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DOI：
10.1371/journal.pbio.1001808
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发表时间：
2014-03
期刊：
影响因子：
9.8
通讯作者：
Prevot V
中科院分区：
文献类型：
--
作者：
Giacobini P;Parkash J;Campagne C;Messina A;Casoni F;Vanacker C;Langlet F;Hobo B;Cagnoni G;Gallet S;Hanchate NK;Mazur D;Taniguchi M;Mazzone M;Verhaagen J;Ciofi P;Bouret SG;Tamagnone L;Prevot V
内皮细胞来源的Sema3A促进轴突生长和可塑性，从而调节成年啮齿动物大脑中神经激素的释放，以响应卵巢周期。神经毛细蛋白-1(Nrp1)指导神经系统和血管系统的发育，但它在成熟大脑中的作用仍有待探索。在这里，我们报道了成年血管内皮细胞表达65 kDa的Sema3A，Nrp1的配体，在卵巢周期中受到调节，并促进下丘脑神经元分泌促性腺激素释放激素(GnRH)的轴突萌发，GnRH是控制生殖的神经肽。GnRH神经元中Sema3A/Nrp1信号的抑制和Nrp1的条件性缺失均可对抗Sema3A诱导的轴突萌发。此外，体内局部注射Nrp1或Sema3A中和抗体会扰乱卵巢周期。最后，静脉注射重组TAT-CRE蛋白选择性中和成年Sema3a loxP/loxP小鼠内皮细胞Sema3A信号，可能是通过干扰GnRH释放到下丘脑-脑垂体门系统，改变排卵前黄体激素激增的幅度。我们的结果确定了65 kDa Sema3A-Nrp1信号在诱导轴突生长中的一个先前未知的功能，并提出了内皮细胞积极参与成年中枢神经系统特定功能区的突触可塑性，从而控制生殖等关键生理功能的可能性。在发育中的胚胎中，内皮细胞释放趋化信号，如Semaphorin 3A(Sema3A)，当其受体Neuropilin-1(Nrp1)激活时，调节神经元迁移和轴突引导。然而，成人大脑中的内皮细胞是否保留了分泌影响神经功能的分子的能力尚不清楚。在这里，我们展示了在成年啮齿动物的大脑中，血管内皮细胞释放Sema3A，释放的量受到排卵周期的调节。Sema3A反过来又促进下丘脑神经元轴突的生长，这些轴突表达Neuropilin-1，朝向门静脉血管内皮壁。这些神经元在那里释放控制生殖的神经肽：促性腺激素释放激素(GnRH)。值得注意的是，这种内皮细胞介导的GnRH轴突的萌发调节着发情周期的关键阶段，即发情前期，当GnRH的激增触发排卵时，神经肽的释放。因此，通过促进成年大脑中GnRH轴突的生长，Sema3A/Neuropilin-1在协调生殖的中枢控制中发挥着关键作用。我们的结果提出了一种模型，在该模型中，血管内皮细胞是动态信号组件，将外周信息传递给大脑，以控制关键的生理功能，包括物种生存。
Endothelial-cell–derived Sema3A promotes axonal outgrowth and plasticity and thereby regulates neurohormone release in the adult rodent brain in response to the ovarian cycle. Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3a loxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction. In the developing embryo, endothelial cells release chemotropic signals such as Semaphorin 3A (Sema3A) that, upon activation of its receptor Neuropilin-1 (Nrp1), regulate neuronal migration and axon guidance. However, whether endothelial cells in the adult brain retain the ability to secrete molecules that influence neuronal function is unknown. Here we show in the adult brain of rodents that vascular endothelial cells release Sema3A and that the amount released is regulated by the ovulatory cycle. Sema3A, in turn, promotes the outgrowth of axons of hypothalamic neurons that express Neuropilin-1 towards the endothelial wall of portal blood vessels. These neurons release there the neuropeptide that controls reproduction: gonadotropin-releasing hormone (GnRH). Notably, this endothelial-cell-mediated sprouting of GnRH axons regulates neuropeptide release at a key stage of the estrous cycle, the proestrus, when the surge of GnRH triggers ovulation. Thus, by promoting GnRH axonal growth in the adult brain, Sema3A/Neuropilin-1 plays a pivotal role in orchestrating the central control of reproduction. Our results suggest a model in which vascular endothelial cells are dynamic signaling components that relay peripheral information to the brain to control key physiological functions, including species survival.
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影响因子：
4.5
作者：
Hanchate NK;Giacobini P;Lhuillier P;Parkash J;Espy C;Fouveaut C;Leroy C;Baron S;Campagne C;Vanacker C;Collier F;Cruaud C;Meyer V;García-Piñero A;Dewailly D;Cortet-Rudelli C;Gersak K;Metz C;Chabrier G;Pugeat M;Young J;Hardelin JP;Prevot V;Dodé C
通讯作者：
Dodé C
影响因子：
7.8
作者：
Giacobini, Paolo;Messina, Andrea;Morello, Francesca;Ferraris, Nicoletta;Corso, Simona;Penachioni, Junia;Giordano, Silvia;Tamagnone, Luca;Fasolo, Aldo
通讯作者：
Fasolo, Aldo
影响因子：
4.8
作者：
de Seranno, Sandrine;de Tassigny, Xavier d'Anglemont;Prevot, Vincent
通讯作者：
Prevot, Vincent
影响因子：
4.8
作者：
Givalois, L;Arancibia, S;Tapia-Arancibia, L
通讯作者：
Tapia-Arancibia, L
影响因子：
3.5
作者：
Cariboni, Anna;Davidson, Kathryn;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana