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PLoS Biol. 2014 Mar 11;12(3):e1001808. doi: 10.1371/journal.pbio.1001808. eCollection 2014 Mar.

Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.

Author information

1
INSERM, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the Postnatal Brain, Lille, France; UDSL, School of Medicine, Place de Verdun, Lille, France; Institut de Médecine Prédictive et de Recherche Thérapeutique, IFR114, Lille, France.
2
Netherlands institute for Neuroscience, Amsterdam, The Netherlands; Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
3
Candiolo Cancer Institute - FPO (IRCCS) and University of Torino, Department of Oncology, Candiolo, Italy.
4
Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
5
Versalius Research Center, VIB, Laboratory of Molecular Oncology and Angiogenesis, Leuven, Belgium; KU Keuven, Versalius Research Center, Leuven, Belgium.
6
INSERM, Neurocentre Magendie, U862, Université de Bordeaux, Bordeaux, France.
7
INSERM, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the Postnatal Brain, Lille, France; UDSL, School of Medicine, Place de Verdun, Lille, France; Institut de Médecine Prédictive et de Recherche Thérapeutique, IFR114, Lille, France; The Saban Research Institute, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California, United States of America.

Abstract

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/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.

PMID:
24618750
PMCID:
PMC3949669
DOI:
10.1371/journal.pbio.1001808
[Indexed for MEDLINE]
Free PMC Article

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