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1. PARP3 supervises G9a-mediated repression of adhesion and hypoxia-responsive genes in glioblastoma cells

Author

Leonel Nguekeu-Zebaze, Najat Hanini, Aurélia Noll, Nadège Wadier, Jean-Christophe Amé, Lisa Roegel, Françoise Dantzer, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV6-0003,ARREPRESS,Bases moléculaires et impact physiologique de la répression des gènes par les récepteurs de l'acide rétinoïque(2013), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), and European Project: 331687,EC:FP7:PEOPLE,FP7-PEOPLE-2012-IEF,INVIVO_RA_NONCANON(2013)

Subjects
Multidisciplinary, Brain Neoplasms, Lysine, Tumor Suppressor Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Methyltransferases, Complement C9, Histones, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Basic Helix-Loop-Helix Transcription Factors, Humans, Poly(ADP-ribose) Polymerases, Glioblastoma, Hypoxia
Abstract

In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblastoma, the most aggressive type of brain cancer. The absence of PARP3 did not alter cell proliferation nor the in vivo tumorigenic potential of glioblastoma cells. We identified a physical and functional interaction of PARP3 with the histone H3 lysine 9 methyltransferase G9a. We show that PARP3 helps to adjust G9a-dependent repression of the adhesion genes Nfasc and Parvb and the hypoxia-responsive genes Hif-2α, Runx3, Mlh1, Ndrg1, Ndrg2 and Ndrg4. Specifically for Nfasc, Parvb and Ndrg4, PARP3/G9a cooperate for an adjusted establishment of the repressive mark H3K9me2. While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.

Published
2022
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2. Absence of Testicular Estrogen Leads to Defects in Spermatogenesis and Increased Semen Abnormalities in Male Rabbits

Author

Aurélie Dewaele, Emilie Dujardin, Marjolaine André, Audrey Albina, Hélène Jammes, Frank Giton, Eli Sellem, Geneviève Jolivet, Eric Pailhoux, Maëlle Pannetier, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, ANR-09-GENM-0009,GENIDOV,Réseaux géniques impliqués dans la différenciation ovarienne chez la chèvre et la souris(2009), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-20-CE14-0022,ARDIGERM,Acide rétinoïque dans la différenciation des cellules germinales et la méiose(2020), BREED, INRAE, Génomique et biotechnologies végétales - Réseaux géniques impliqués dans la différenciation ovarienne chez la chèvre et la souris - - GENIDOV2009 - ANR-09-GENM-0009 - GENOM-BTV - VALID, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, and Acide rétinoïque dans la différenciation des cellules germinales et la méiose - - ARDIGERM2020 - ANR-20-CE14-0022 - AAPG2020 - VALID

Subjects
CYP19A1 knock-out, male fertility, testicular estrogens, epididymis, spermatogenesis, sperm maturation, DNA methylation, Male, Mammals, Estrogens, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Semen, Testis, Genetics, Sperm Motility, Humans, Animals, Female, Rabbits, Genetics (clinical), [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract

Estrogens are steroid hormones produced by the aromatization of androgens by the aromatase enzyme, encoded by the CYP19A1 gene. Although generally referred to as “female sex hormones”, estrogen is also produced in the adult testes of many mammals, including humans. To better understand the function of estrogens in the male, we used the rabbit model which is an important biomedical model. First, the expression of CYP19A1 transcripts was localized mainly in meiotic germ cells. Thus, testicular estrogen appears to be produced inside the seminiferous tubules. Next, the cells expressing ESR1 and ESR2 were identified, showing that estrogens could exert their function on post-meiotic germ cells in the tubules and play a role during sperm maturation, since ESR1 and ESR2 were detected in the cauda epididymis. Then, CRISPR/Cas9 CYP19A1−/− genetically modified rabbits were analyzed. CYP19A1−/− males showed decreased fertility with lower sperm count associated with hypo-spermatogenesis and lower spermatid number. Germ/sperm cell DNA methylation was unchanged, while sperm parameters were affected as CYP19A1−/− males exhibited reduced sperm motility associated with increased flagellar defects. In conclusion, testicular estrogens could be involved in the spermatocyte–spermatid transition in the testis, and in the acquisition of sperm motility in the epididymis.

Published
2022
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3. Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation in rabbits

Author

Eloïse Airaud, Aurélie Dewaele, Laurent Boulanger, Nathalie Daniel-Carlier, Frank Giton, Beatrice Mandon-Pepin, Maëlle Pannetier, Geneviève Jolivet, Cloé Pierson, Eric Pailhoux, Erwana Harscoët, Nathalie Daniel, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), ANR-09-GENM-0009,GENIDOV,Réseaux géniques impliqués dans la différenciation ovarienne chez la chèvre et la souris(2009), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, This study was supported by ANR grants (GENIDOV:ANR-09-GENM-009, ARGONADS: ANR-13-BSV2-0017, ARDIGERM: ANR-2020-CE14), and the CELPHEDIA infrastructure (CELPHEDIA France, 2017)., ANR-20-CE14-0022,ARDIGERM,Acide rétinoïque dans la différenciation des cellules germinales et la méiose(2020), Jolivet, Geneviève, Génomique et biotechnologies végétales - Réseaux géniques impliqués dans la différenciation ovarienne chez la chèvre et la souris - - GENIDOV2009 - ANR-09-GENM-0009 - GENOM-BTV - VALID, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, and Acide rétinoïque dans la différenciation des cellules germinales et la méiose - - ARDIGERM2020 - ANR-20-CE14-0022 - AAPG2020 - VALID

Subjects
Anti-Mullerian Hormone, Sex Differentiation, Somatic cell, [SDV]Life Sciences [q-bio], sex determination, AROMATASE, 0302 clinical medicine, INDEL Mutation, Ovarian Follicle, TALEN, Testosterone, Aromatase, Antrum, [SDV.BDD]Life Sciences [q-bio]/Development Biology, media_common, 0303 health sciences, 030219 obstetrics & reproductive medicine, Estradiol, biology, Gene Expression Regulation, Developmental, Cell Differentiation, Phenotype, medicine.anatomical_structure, Female, Cytochrome P450 Family 19, Rabbits, AcademicSubjects/MED00250, Research Article, Ovulation, endocrine system, Gonad, media_common.quotation_subject, rabbit, Andrology, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, CYP19A1, Gonads, Ovarian reserve, Cell Proliferation, 030304 developmental biology, Fetus, Sexual differentiation, Gene Expression Profiling, Estrogens, Sex Determination Processes, CYP26A1, biology.protein, ovary
Abstract

AROMATASE, encoded by the CYP19A1 gene, is the cytochrome enzyme responsible for the synthesis of estrogens in vertebrates. In most mammals a peak of expression of the CYP19A1 gene occurs in the fetal XX gonad when sexual differentiation starts up. To elucidate the role of this peak, we produced 3 lines of TALEN genetically edited CYP19A1 KO rabbits, that were void of any production of estradiol. All KO XX rabbits developed as females, with aberrantly small sized ovaries at adulthood, an almost empty reserve of primordial follicles and very few large antrum follicles. Ovulation never occurred. Our histological, immunohistological and transcriptomic analyses showed that the surge of estradiol in the XX fetal rabbit gonad is dispensable for its determination as an ovary, or for meiosis. However, it is mandatory for the high proliferation and differentiation of both somatic and germ cells, and consequently for the establishment of the ovarian reserve.

Published
2021
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4. Arrest of WNT/β-catenin signaling enables the transition from pluripotent to differentiated germ cells in mouse ovaries

Author

Morgane Le Rolle, Anne-Amandine Chassot, Pam Siggers, Filippo Massa, Marie-Christine Chaboissier, Bon-Kyoung Koo, Andreas Schedl, Hans Clevers, Agnès Loubat, Laurent Turchi, Andy Greenfield, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), MRC Harwell Institute [UK], Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), ANR-20-CE14-0022,ARDIGERM,Acide rétinoïque dans la différenciation des cellules germinales et la méiose(2020), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Chaboissier, Marie-Christine, Acide rétinoïque dans la différenciation des cellules germinales et la méiose - - ARDIGERM2020 - ANR-20-CE14-0022 - AAPG2020 - VALID, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Hubrecht Institute for Developmental Biology and Stem Cell Research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and CHASSOT, Anne Amandine

Subjects
Male, Pluripotent Stem Cells, germ cells, beta Catenin/genetics, Pluripotency & Differentiation, [SDV]Life Sciences [q-bio], Biology, Inbred C57BL, 03 medical and health sciences, Mice, 0302 clinical medicine, Meiosis, Primordial germ cell, medicine, Animals, Germ Cells/cytology, Wnt Proteins/genetics, Gametogenesis, beta Catenin, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Wnt signaling pathway, Cell Differentiation, Pluripotent Stem Cells/cytology, WNT/β-catenin, differentiation, Cell cycle, Biological Sciences, POU5F1/OCT4, Embryonic stem cell, Cell biology, Sexual reproduction, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Wnt Proteins, medicine.anatomical_structure, Female, ovary, Signal transduction, Octamer Transcription Factor-3, 030217 neurology & neurosurgery, Germ cell, Octamer Transcription Factor-3/genetics, Developmental Biology
Abstract

Significance In the mammalian ovary, primordial germ cells maintain a genomic program associated with pluripotency until they stop proliferating, move toward oogenesis, and enter meiosis. The molecular mechanisms that enable primordial germ cells to exit pluripotency and enter meiosis in a timely manner are unclear, and their identification represents a major challenge in reproductive biology because the fertility of each individual depends on this. Evidence that cessation of germ cell proliferation is a cell-autonomous event, unrelated to the number of cell divisions, led to a search for an intrinsic timing mechanism that has long remained elusive. We describe here that WNT/β-catenin signaling regulates this timing and coordinates the transition from pluripotent to gametogenesis-competent germ cells., Germ cells form the basis for sexual reproduction by producing gametes. In ovaries, primordial germ cells exit the cell cycle and the pluripotency-associated state, differentiate into oogonia, and initiate meiosis. Despite the importance of germ cell differentiation for sexual reproduction, signaling pathways regulating their fate remain largely unknown. Here, we show in mouse embryonic ovaries that germ cell–intrinsic β-catenin activity maintains pluripotency and that its repression is essential to allow differentiation and meiosis entry in a timely manner. Accordingly, in β-catenin loss-of-function and gain-of-function mouse models, the germ cells precociously enter meiosis or remain in the pluripotent state, respectively. We further show that interaction of β-catenin and the pluripotent-associated factor POU5F1 in the nucleus is associated with germ cell pluripotency. The exit of this complex from the nucleus correlates with germ cell differentiation, a process promoted by the up-regulation of Znrf3, a negative regulator of WNT/β-catenin signaling. Together, these data identify the molecular basis of the transition from primordial germ cells to oogonia and demonstrate that β-catenin is a central gatekeeper in ovarian differentiation and gametogenesis.

Published
2021
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5. Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary

Author

Morgane Le Rolle, Isabelle Stévant, Andreas Schedl, Marie-Christine Chaboissier, Norbert B. Ghyselinck, Eric Pailhoux, Fabio Da Silva, Geneviève Jolivet, Anne-Amandine Chassot, Jean-Marie Guigonis, Serge Nef, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Genève (UNIGE), Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Medical School of the University of Geneva, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), French National Research Agency (ANR)ANR-13-BSV2-0017-02 ARGONADSANR-11-LABX-0028-01ANR-18-CE14-0012 SexSpecsLa Ligue Nationale Contre le Cancer (Equipe Labelisée Ligue Nationale Contre le Cancer), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-18-CE14-0012,Sex-Specs,Homeostasie tissulaire selon le sex et son impact sur les maladies surrénaliennes(2018), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Department of Genetic Medicine and Development [Geneva], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Chaboissier, Marie-Christine, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Homeostasie tissulaire selon le sex et son impact sur les maladies surrénaliennes - - Sex-Specs2018 - ANR-18-CE14-0012 - AAPG2018 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Université Nice Sophia Antipolis (1965 - 2019) (UNS), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), ANR-13-BSV2-0017-02 ARGONADSANR-11-LABX-0028-01ANR-18-CE14-0012 SexSpecsLa Ligue Nationale Contre le Cancer (Equipe Labelisée), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Retinoic acid, Endogeny, Oogenesis, chemistry.chemical_compound, 0302 clinical medicine, CYP26B1, PRIMORDIAL GERM-CELLS, BINDING, ddc:576.5, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Research Articles, Mammals, 0303 health sciences, Multidisciplinary, integumentary system, SciAdv r-articles, CELL SEX DETERMINATION, LINEAGE, MEIOSIS, OOGENESIS, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, DIFFERENTIATION, Female, Research Article, EXPRESSION, FATE, Ovary, Tretinoin, Biology, ALDH1A2, 03 medical and health sciences, Meiosis, medicine, Animals, Gene, neoplasms, 030304 developmental biology, organic chemicals, Proteins, Cell Biology, GENE, biological factors, ALDH1A1, body regions, MICE, Germ Cells, chemistry, biology.protein, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Retinoic acid synthesis is not essential for meiosis in fetal ovaries, challenging the dogma about the meiosis-inducing factors., In mammals, the timing of meiosis entry is regulated by signals from the gonadal environment. All-trans retinoic acid (ATRA) signaling is considered the key pathway that promotes Stra8 (stimulated by retinoic acid 8) expression and, in turn, meiosis entry. This model, however, is debated because it is based on analyzing the effects of exogenous ATRA on ex vivo gonadal cultures, which not accurately reflects the role of endogenous ATRA. Aldh1a1 and Aldh1a2, two retinaldehyde dehydrogenases synthesizing ATRA, are expressed in the mouse ovaries when meiosis initiates. Contrary to the present view, here, we demonstrate that ATRA-responsive cells are scarce in the ovary. Using three distinct gene deletion models for Aldh1a1;Aldh1a2;Aldh1a3, we show that Stra8 expression is independent of ATRA production by ALDH1A proteins and that germ cells progress through meiosis. Together, these data demonstrate that ATRA signaling is dispensable for instructing meiosis initiation in female germ cells.

Published
2020
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6. NRG1 signalling regulates the establishment of Sertoli cell stock in the mouse testis

Author

Gregoire, Elodie P, Stevant, Isabelle, Chassot, Anne-Amandine, Martin, Luc, Lachambre, Simon, Mondin, Magali, de Rooij, Dirk G, Nef, Serge, Chaboissier, Marie-Christine, Sub Developmental Biology, Developmental Biology, Sub Developmental Biology, Developmental Biology, Chaboissier, Marie-Christine, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université de Genève = University of Geneva (UNIGE), Utrecht University [Utrecht], ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), CHASSOT, Anne Amandine, Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Aselta Nanographics, MRI-Montpellier RIO Imaging, Department of Genetic Medicine and Development [Geneva], Génétique du développement normal et pathologique, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Academic Medical Center, Amsterdam Reproduction & Development (AR&D), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Université de Genève (UNIGE)

Subjects
0301 basic medicine, Male, endocrine system, medicine.drug_class, medicine.medical_treatment, Neuregulin-1, [SDV]Life Sciences [q-bio], Cell, Proliferation, Cell Count, Biology, Biochemistry, Progenitor cells, 03 medical and health sciences, Endocrinology, mental disorders, Testis, medicine, Animals, ddc:576.5, Progenitor cell, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Nrg1, Sertoli Cells, Leydig cell, urogenital system, Growth factor, Stem Cells, Cell Differentiation, Sex Determination Processes, Androgen, Sertoli cell, Hypoplasia, Cell biology, ErbB Receptors, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Knockout mouse, Female, Thrombospondins, Gene Deletion, Signal Transduction
Abstract

International audience; Testis differentiation requires high levels of proliferation of progenitor cells that give rise to two cell lineages forming the testis, the Sertoli and the Leydig cells. Hence defective cell cycling leads to testicular dysgenesis that has profound effects on androgen production and fertility. The growth factor NRG1 has been implicated in adult Leydig cell proliferation, but a potential function in the fetal testis has not been analysed to date. Here we show that Nrg1 and its receptors ErbB2/3 are already expressed in early gonadal development. Using tissue-specific deletion, we further demonstrate that Nrg1 is required in a dose-dependent manner to induce proliferation of Sertoli progenitor cells and then differentiated Sertoli cells. As a result of reduced numbers of Sertoli cells, Nrg1 knockout mice display a delay in testis differentiation and defects in sex cord partitioning. Taken together Nrg1 signalling is essential for the establishment of the stock of Sertoli cells and thus required to prevent testicular hypoplasia.

Published
2018
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7. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor

Author

Muriel Klopfenstein, Christine Dennefeld, Irwin Davidson, Norbert B. Ghyselinck, Marius Teletin, Aurore Gely-Pernot, Mathilde Raverdeau, Manuel Mark, Gérard Benoit, Betty Féret, Nadège Vernet, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Santé Environnement Travail et Génie Sanitaire (DSETGS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 - Faculté des sciences et technologies (UCBL FST), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, This work was supported by grants from CNRS, INSERM, UNISTRA, Agence Nationale pour la Recherche (ANR 09-BLAN-0282, 10-BLAN-1239, 13-BSV2-0017), Fondation pour la Recherche Médicale (FDT20110922849, DEQ20071210544) and European community (FP7-PEOPLE-2012-IEF Marie Curie action, project #331687). It was also supported in part by the grant ANR-10-LABX-0030-INRT under the frame program Investissements d'Avenir labeled ANR-10-IDEX-0002-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-09-BLAN-0282,NUREDIM,Bases structurales et implications biologiques in vivo des mécanismes de l'homodimérisation des récepteurs nucléaires non stéroïdiens(2009), ANR-10-BLAN-1239,molmechmeiosis,Mécanismes moléculaires contrôlant l'entrée en méiose chez les mammifères(2010), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), European Project: 331687,EC:FP7:PEOPLE,FP7-PEOPLE-2012-IEF,INVIVO_RA_NONCANON(2013), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université Claude Bernard Lyon 1 - Faculté des sciences (UCBL FS)

Subjects
Male, Cancer Research, Cellular differentiation, Sertoli cells, Retinoic acid, Epithelium, chemistry.chemical_compound, Mice, Spermatocytes, Cell differentiation, Testes, Genetics (clinical), [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Gene Expression Regulation, Developmental, Sertoli cell, Spermatids, Cell biology, DNA-Binding Proteins, Meiosis, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, Germ cell, medicine.drug, Research Article, endocrine system, lcsh:QH426-470, Tretinoin, Biology, Cell fate determination, Retinoid X receptor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Germ cells, Animals, Humans, Spermatogenesis, Molecular Biology, Transcription factor, neoplasms, Ecology, Evolution, Behavior and Systematics, urogenital system, organic chemicals, Molecular biology, biological factors, Spermatogonia, lcsh:Genetics, Retinoid X Receptors, chemistry, Transcription Factors
Abstract

All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells., Author Summary Differentiation of spermatozoa from immature germ cells, called spermatogonia, critically depends on retinoic acid (ATRA), the active metabolite of vitamin A that acts though binding to nuclear receptors called RXR and RAR. To understand the mechanism by which ATRA control germ cell differentiation, we generated mice simultaneously lacking all RXR or all RAR specifically in spermatogonia. From their phenotypic analysis, we demonstrate that meiosis does not require a RAR/RXR-dependent pathway in germ cells and propose that this process is either ATRA-independent or requires an ATRA signal originating from somatic cells. We also show that RXR, in the form of dimers with RAR, can drive spermatogonia differentiation through binding to a regulatory region located in the Sall4 gene. This finding is significant, as the transcription factor encoded by Sall4 is known to regulate the expression of KIT, a key tyrosine kinase receptor which is frequently deregulated in testicular cancer.

Published
2015
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8. Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors

Author

Norbert B. Ghyselinck, Chloé Mayère, William Magnant, Violaine Alunni, Manuel Mark, Muriel Klopfenstein, Serge Nef, Betty Féret, Sirine Souali-Crespo, Diana Condrea, Marius Teletin, Nadège Vernet, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV6-0003,ARREPRESS,Bases moléculaires et impact physiologique de la répression des gènes par les récepteurs de l'acide rétinoïque(2013), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), and European Project: 331687,EC:FP7:PEOPLE,FP7-PEOPLE-2012-IEF,INVIVO_RA_NONCANON(2013)

Subjects
Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Mutant, Retinoic acid, Ovary, Tretinoin, Biology, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Fetus, Meiosis, medicine, Animals, ddc:576.5, Receptor, neoplasms, Research Articles, 030304 developmental biology, Mammals, 0303 health sciences, Multidisciplinary, organic chemicals, Gene targeting, SciAdv r-articles, Null allele, biological factors, Cell biology, medicine.anatomical_structure, chemistry, Nuclear receptor, embryonic structures, Female, 030217 neurology & neurosurgery, Research Article, Developmental Biology
Abstract

Functional oocytes are produced in the complete absence of retinoic acid receptors., Gametes are generated through a specialized cell differentiation process, meiosis, which, in ovaries of most mammals, is initiated during fetal life. All-trans retinoic acid (ATRA) is considered as the molecular signal triggering meiosis initiation. In the present study, we analyzed female fetuses ubiquitously lacking all ATRA nuclear receptors (RAR), obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Unexpectedly, mutant oocytes robustly expressed meiotic genes, including the meiotic gatekeeper STRA8. In addition, ovaries from mutant fetuses grafted into adult recipient females yielded offspring bearing null alleles for all Rar genes. Thus, our results show that RAR are fully dispensable for meiotic initiation, as well as for the production of functional oocytes. Assuming that the effects of ATRA all rely on RAR, our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary. It therefore revives the search for the meiosis-inducing substance.

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