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

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; J. Verhaagen; Philippe Ciofi; Sébastien G Bouret; Luca Tamagnone; Vincent Prevot

doi:10.1371/journal.pbio.1001808

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

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, J. Verhaagen, Philippe Ciofi, Sébastien G Bouret, Luca Tamagnone, Vincent Prevot

Netherlands Institute for Neuroscience (NIN)

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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.

Original language	English
Pages (from-to)	e1001808
Journal	PLoS Biology
Volume	12
Issue number	3
DOIs	https://doi.org/10.1371/journal.pbio.1001808
Publication status	Published - Mar 2014

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Giacobini, P., Parkash, J., Campagne, C., Messina, A., Casoni, F., Vanacker, C., Langlet, F., Hobo, B., Cagnoni, G., Gallet, S., Hanchate, N. K., Mazur, D., Taniguchi, M., Mazzone, M., Verhaagen, J., Ciofi, P., Bouret, S. G., Tamagnone, L., & Prevot, V. (2014). Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A. PLoS Biology, 12(3), e1001808. https://doi.org/10.1371/journal.pbio.1001808

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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.",

author = "Paolo Giacobini and Jyoti Parkash and C{\'e}line Campagne and Andrea Messina and Filippo Casoni and Charlotte Vanacker and Fanny Langlet and Barbara Hobo and Gabriella Cagnoni and Sarah Gallet and Hanchate, {Naresh Kumar} and Dani{\`e}le Mazur and Masahiko Taniguchi and Massimiliano Mazzone and J. Verhaagen and Philippe Ciofi and Bouret, {S{\'e}bastien G} and Luca Tamagnone and Vincent Prevot",

year = "2014",

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doi = "10.1371/journal.pbio.1001808",

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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 2014, 'Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A', PLoS Biology, vol. 12, no. 3, pp. e1001808. https://doi.org/10.1371/journal.pbio.1001808

TY - JOUR

T1 - Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A

AU - Giacobini, Paolo

AU - Parkash, Jyoti

AU - Campagne, Céline

AU - Messina, Andrea

AU - Casoni, Filippo

AU - Vanacker, Charlotte

AU - Langlet, Fanny

AU - Hobo, Barbara

AU - Cagnoni, Gabriella

AU - Gallet, Sarah

AU - Hanchate, Naresh Kumar

AU - Mazur, Danièle

AU - Taniguchi, Masahiko

AU - Mazzone, Massimiliano

AU - Verhaagen, J.

AU - Ciofi, Philippe

AU - Bouret, Sébastien G

AU - Tamagnone, Luca

AU - Prevot, Vincent

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pbio.1001808

DO - 10.1371/journal.pbio.1001808

M3 - Article

C2 - 24618750

SN - 1544-9173

VL - 12

SP - e1001808

JO - PLoS Biology

JF - PLoS Biology

IS - 3

ER -

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

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