title: Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.
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.
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giacobini
authors.affiliation: 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.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Campagne
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Messina
authors.affiliation: 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.
authors.forename: Filippo
authors.initials: F
authors.lastname: Casoni
authors.affiliation: 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.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vanacker
authors.affiliation: 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.
authors.forename: Fanny
authors.initials: F
authors.lastname: Langlet
authors.affiliation: Netherlands institute for Neuroscience, Amsterdam, The Netherlands; Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hobo
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS) and University of Torino, Department of Oncology, Candiolo, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cagnoni
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gallet
authors.affiliation: 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.
authors.forename: Naresh Kumar
authors.initials: NK
authors.lastname: Hanchate
authors.affiliation: 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.
authors.forename: Danièle
authors.initials: D
authors.lastname: Mazur
authors.affiliation: Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Versalius Research Center, VIB, Laboratory of Molecular Oncology and Angiogenesis, Leuven, Belgium; KU Keuven, Versalius Research Center, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Netherlands institute for Neuroscience, Amsterdam, The Netherlands; Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: INSERM, Neurocentre Magendie, U862, Université de Bordeaux, Bordeaux, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ciofi
authors.affiliation: 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.
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Bouret
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS) and University of Torino, Department of Oncology, Candiolo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D030762:Estrous Cycle / Q000378:metabolism; D005298:Fertility / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D007986:Luteinizing Hormone / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039942:Neuropilin-1 / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D008024:Ligands; D040121:Semaphorin-3A; D039942:Neuropilin-1; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone