Brain Endothelial Cells Control Fertility through Ovarian-Steroid-Dependent Release of Semaphorin 3A

Luca Tamagnone, Paolo Giacobini, Jyoti Parkash, Céline Campagne, Andrea Messina, Filippo Casoni, Charlotte Vanacker, Fanny Langlet, Barbara Hobo, Gabriella Cagnoni, Sarah Gallet, Naresh Kumar Hanchate, Danièle Mazur, Masahiko Taniguchi, Massimiliano Mazzone, Joost Verhaagen, Philippe Ciofi, Sébastien G. Bouret, Vincent Prevot

Research output: Contribution to journalArticle

38 Citations (Scopus)


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 Sema3aloxP/loxPmice 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. © 2014 Giacobini et al.
Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalPLoS Biology
Publication statusPublished - 2014


  • Neuropilin-1 (Nrp1)
  • Sema3A
  • gonadotropin-releasing hormone (GnRH)

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