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p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons

p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus...

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Autores principales: Camera, Mattia, Russo, Isabella, Zamboni, Valentina, Ammoni, Alessandra, Rando, Simona, Morellato, Alessandro, Cimino, Irene, Angelini, Costanza, Giacobini, Paolo, Oleari, Roberto, Amoruso, Federica, Cariboni, Anna, Franceschini, Isabelle, Turco, Emilia, Defilippi, Paola, Merlo, Giorgio R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884249/
https://www.ncbi.nlm.nih.gov/pubmed/35237119
http://dx.doi.org/10.3389/fnins.2022.744693
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author Camera, Mattia
Russo, Isabella
Zamboni, Valentina
Ammoni, Alessandra
Rando, Simona
Morellato, Alessandro
Cimino, Irene
Angelini, Costanza
Giacobini, Paolo
Oleari, Roberto
Amoruso, Federica
Cariboni, Anna
Franceschini, Isabelle
Turco, Emilia
Defilippi, Paola
Merlo, Giorgio R.
author_facet Camera, Mattia
Russo, Isabella
Zamboni, Valentina
Ammoni, Alessandra
Rando, Simona
Morellato, Alessandro
Cimino, Irene
Angelini, Costanza
Giacobini, Paolo
Oleari, Roberto
Amoruso, Federica
Cariboni, Anna
Franceschini, Isabelle
Turco, Emilia
Defilippi, Paola
Merlo, Giorgio R.
author_sort Camera, Mattia
collection PubMed
description p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.
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spelling pubmed-88842492022-03-01 p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons Camera, Mattia Russo, Isabella Zamboni, Valentina Ammoni, Alessandra Rando, Simona Morellato, Alessandro Cimino, Irene Angelini, Costanza Giacobini, Paolo Oleari, Roberto Amoruso, Federica Cariboni, Anna Franceschini, Isabelle Turco, Emilia Defilippi, Paola Merlo, Giorgio R. Front Neurosci Neuroscience p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility. Frontiers Media S.A. 2022-02-14 /pmc/articles/PMC8884249/ /pubmed/35237119 http://dx.doi.org/10.3389/fnins.2022.744693 Text en Copyright © 2022 Camera, Russo, Zamboni, Ammoni, Rando, Morellato, Cimino, Angelini, Giacobini, Oleari, Amoruso, Cariboni, Franceschini, Turco, Defilippi and Merlo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Camera, Mattia
Russo, Isabella
Zamboni, Valentina
Ammoni, Alessandra
Rando, Simona
Morellato, Alessandro
Cimino, Irene
Angelini, Costanza
Giacobini, Paolo
Oleari, Roberto
Amoruso, Federica
Cariboni, Anna
Franceschini, Isabelle
Turco, Emilia
Defilippi, Paola
Merlo, Giorgio R.
p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title_full p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title_fullStr p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title_full_unstemmed p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title_short p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons
title_sort p140cap controls female fertility in mice acting via glutamatergic afference on hypothalamic gonadotropin-releasing hormone neurons
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884249/
https://www.ncbi.nlm.nih.gov/pubmed/35237119
http://dx.doi.org/10.3389/fnins.2022.744693
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