130 results on '"Livera G"'
Search Results
2. Effets des estrogènes sur le développement du testicule pendant la vie fœtale et néonatale
- Author
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Habert, R., Delbes, G., Duquenne, C., Livera, G., and Levacher, C.
- Published
- 2006
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3. Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis
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Le Bouffant, R., Guerquin, M.J., Duquenne, C., Frydman, N., Coffigny, H., Rouiller-Fabre, V., Frydman, R., Habert, R., and Livera, G.
- Published
- 2010
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4. Inactivation of the Mouse Adenylyl Cyclase 3 Gene Disrupts Male Fertility and Spermatozoon Function
- Author
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Livera, G, Xie, F, Garcia, M A., Jaiswal, B, Chen, J, Law, E, Storm, D R., and Conti, M
- Published
- 2005
5. Development of the foetal and neonatal testis
- Author
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Rouiller-Fabre, V., Levacher, C., Pairault, C., Racine, C., Moreau, E., Olaso, R., Livera, G., Migrenne, S., Delbes, G., and Habert, R.
- Published
- 2003
6. Ovogenèse in vitro : quel chemin parcouru ?
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Arkoun, B., primary and Livera, G., additional
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- 2018
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7. Culture cellulaire de testicule et d'ovaire pour l'étude de la fonction de reproduction
- Author
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Pascal Froment, Quignot, N., Legendre, A., Rouiller-Fabre, V., Livera, G., Joëlle Dupont, Habert, R., Lamazurier, E., Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), LA-SER Analytica, U967, Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Diderot - Paris 7 (UPD7), Institut National de l'Environnement Industriel et des Risques, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de radiotoxicologie et radiobiologie expérimentale (IRSN/PRP-HOM/SRBE/LRTOX), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Institut National de l'Environnement Industriel et des Risques (INERIS), Georgia Barlovatz-Meimon, Xavier Ronot, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
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reproduction ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,culture cellulaire ,ovaire ,microbial culture ,testicule ,ovary ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,testis ,gonad ,gonade - Abstract
Chapitre 30; Culture cellulaire de testicule et d'ovaire pour l'étude de la fonction de reproduction
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- 2014
8. Loss of the histone chaperone ASF1B reduces female reproductive capacity in mice
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Messiaen, S, primary, Guiard, J, additional, Aigueperse, C, additional, Fliniaux, I, additional, Tourpin, S, additional, Barroca, V, additional, Allemand, I, additional, Fouchet, P, additional, Livera, G, additional, and Vernet, M, additional
- Published
- 2016
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9. Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility
- Author
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Fouchécourt, S, primary, Livera, G, additional, Messiaen, S, additional, Fumel, B, additional, Parent, A-S, additional, Marine, J-C, additional, and Monget, P, additional
- Published
- 2015
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10. Involvement of doublesex and mab-3-related transcription factors in human female germ cell development demonstrated by xenograft and interference RNA strategies
- Author
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Poulain, M., primary, Frydman, N., additional, Tourpin, S., additional, Muczynski, V., additional, Souquet, B., additional, Benachi, A., additional, Habert, R., additional, Rouiller-Fabre, V., additional, and Livera, G., additional
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- 2014
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11. Rad54 is required for the normal development of male and female germ cells and contributes to the maintainance of their genome integrity after genotoxic stress
- Author
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Messiaen, S, primary, Le Bras, A, additional, Duquenne, C, additional, Barroca, V, additional, Moison, D, additional, Déchamps, N, additional, Doussau, M, additional, Bauchet, A-L, additional, Guerquin, M-J, additional, Livera, G, additional, Essers, J, additional, Kanaar, R, additional, Habert, R, additional, and Bernardino-Sgherri, J, additional
- Published
- 2013
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12. Sex-specific differences in fetal germ cell apoptosis induced by ionizing radiation
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Guerquin, M.-J., primary, Duquenne, C., additional, Coffigny, H., additional, Rouiller-Fabre, V., additional, Lambrot, R., additional, Bakalska, M., additional, Frydman, R., additional, Habert, R., additional, and Livera, G., additional
- Published
- 2008
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13. p63 null mutation protects mouse oocytes from radio-induced apoptosis
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Livera, G., primary, Petre-Lazar, B., additional, Guerquin, M.-J., additional, Trautmann, E., additional, Coffigny, H., additional, and Habert, R., additional
- Published
- 2007
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14. Erratum to “A new method for toxicity assays on human and mouse fetal testis” [Biochimie 88(11) (2006) 1831–1835]
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Lambrot, R., primary, Livera, G., additional, Coffigny, H., additional, Pairault, C., additional, Frydman, R., additional, Habert, R., additional, and Rouiller-Fabre, V., additional
- Published
- 2007
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15. Caspase-2 involvement during ionizing radiation-induced oocyte death in the mouse ovary
- Author
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Hanoux, V, primary, Pairault, C, additional, Bakalska, M, additional, Habert, R, additional, and Livera, G, additional
- Published
- 2006
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16. A new method for toxicity assays on human and mouse fetal testis
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Lambrot, R., primary, Livera, G., additional, Coffigny, H., additional, Pairault, C., additional, Frydman, R., additional, Habert, R., additional, and Rouiller-Fabre, V., additional
- Published
- 2006
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17. p63 expression pattern in foetal and neonatal gonocytes after irradiation and role in the resulting apoptosis by using p63 knockout mice
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Petre-Lazar, B., primary, Moreno, S. G., additional, Livera, G., additional, Duquenne, C., additional, Habert, R., additional, and Coffigny, H., additional
- Published
- 2006
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18. Retinoid-Sensitive Steps in Steroidogenesis in Fetal and Neonatal Rat Testes: In Vitro and In Vivo Studies
- Author
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Livera, G., primary, Pairault, C., additional, Lambrot, R., additional, Lelievre-Pegorier, M., additional, Saez, J.M., additional, Habert, R., additional, and Rouiller-Fabre, V., additional
- Published
- 2004
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19. Regulation and perturbation of testicular functions by vitamin A. (Abstracts)
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Livera, G, Rouiller-Fabre, V, and Pairault, C
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Fetus -- Growth ,Vitamin A -- Health aspects -- Physiological aspects ,Testis -- Physiological aspects -- Health aspects ,Health ,Physiological aspects ,Health aspects - Abstract
Livera G, Rouiller-Fabre V, Pairault C, et al. Reproduction 2002; 124:173-180. In addition to playing a fundamental role in very diverse processes such as vision and the growth and differentiation [...]
- Published
- 2002
20. Regulation and perturbation of testicular functions by vitamin A
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Livera, G, primary
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- 2002
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21. Retinoid Receptors Involved in the Effects of Retinoic Acid on Rat Testis Development1
- Author
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Livera, G., primary, Rouiller-Fabre, V., additional, and Habert, R., additional
- Published
- 2001
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22. Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility
- Author
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Fouchécourt, S, Livera, G, Messiaen, S, Fumel, B, Parent, A-S, Marine, J-C, and Monget, P
- Abstract
Beside its well-documented role in carcinogenesis, the function of p53 family has been more recently revealed in development and female reproduction, but it is still poorly documented in male reproduction. We specifically tested this possibility by ablating Mdm2, an E3 ligase that regulates p53 protein stability and transactivation function, specifically in Sertoli cells (SCs) using the AMH-Cre line and created the new SC-Mdm2−/−line. Heterozygous SC-Mdm2−/+adult males were fertile, but SC-Mdm2−/−males were infertile and exhibited: a shorter ano-genital distance, an extra duct along the vas deferens that presents a uterus-like morphology, degenerated testes with no organized seminiferous tubules and a complete loss of differentiated germ cells. In adults, testosterone levels as well as StAR, P450c17 (Cyp17a1) and P450scc (Cyp11a1) mRNA levels decreased significantly, and both plasma LH and FSH levels increased. A detailed investigation of testicular development indicated that the phenotype arose during fetal life, with SC-Mdm2−/−testes being much smaller at birth. Interestingly, Leydig cells remained present until adulthood and fetal germ cells abnormally initiated meiosis. Inactivation of Mdm2 in SCs triggered p53 activation and apoptosis as early as 15.5 days post conception with significant increase in apoptotic SCs. Importantly, testis development occurred normally in SC-Mdm2−/−lacking p53 mice (SC-Mdm2−/−p53−/−) and accordingly, these mice were fertile indicating that the aforementioned phenotypes are entirely p53-dependent. These data not only highlight the importance of keeping p53 in check for proper testicular development and male fertility but also certify the critical role of SCs in the maintenance of meiotic repression.
- Published
- 2016
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23. Effects of retinoids on the meiosis in the fetal rat ovary in culture
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Livera, G, primary
- Published
- 2000
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24. Multiple Effects of Retinoids on the Development of Sertoli, Germ, and Leydig Cells of Fetal and Neonatal Rat Testis in Culture1
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Livera, G., primary, Rouiller-Fabre, V., additional, Durand, P., additional, and Habert, R., additional
- Published
- 2000
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25. Caspase-2 involvement during ionizing radiation-induced oocyte death in the mouse ovary.
- Author
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Hanoux, V., Pairault, C., Bakalska, M., Habert, R., and Livera, G.
- Subjects
ANIMAL infertility ,IMMUNOHISTOCHEMISTRY ,OVUM ,IRRADIATION ,LABORATORY mice - Abstract
In mammals, the pool of primordial follicles at birth is determinant for female fertility. Exposure to IR during oogonia proliferation and the diplotene stages of ovarian development induced the virtual disappearance of primordial follicles in the postnatal ovary, while half the follicular reserve remained present after irradiation during the zygotene/pachytene stages. This sensitivity difference was correlated with the level of caspase-2 expression evaluated by immunohistochemistry. At the diplotene stage, Western blot and caspase activity analysis revealed that caspase-2 was activated 2 h after irradiation and a significant increase in the number of oocytes expressing cleaved caspase-9 and -3 occurred 6 h after treatment. Inhibition of caspase-2 activity prevented the cleavage of caspase-9 and partially prevented the loss of oocytes in response to irradiation. Taken together, our results show that caspase-2-dependent activation of the mitochondrial apoptotic pathway is one of the mechanisms involved in the genotoxic stress-induced depletion of the primordial follicle pool.Cell Death and Differentiation (2007) 14, 671–681. doi:10.1038/sj.cdd.4402052; published online 3 November 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2007
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26. Time- and Dose-Related Effects of Estradiol and Diethylstilbestrol on the Morphology and Function of the Fetal Rat Testis in Culture.
- Author
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Lassurguère, J., Livera, G., Habert, R., and Jégou, B.
- Subjects
ESTRADIOL ,DIETHYLSTILBESTROL ,GENETIC toxicology ,ANIMAL models of toxicology ,ESTROGEN antagonists ,LEYDIG cells ,ORGAN culture - Abstract
The mechanisms underlying the action of estrogens in the fetal testis are still largely obscure. In particular, whether this action is direct or indirect remains largely unexplored. This study was aimed at investigating the effect of estradiol (E
2 ) and diethylstilbestrol (DES) on the testis from 14.5-day-old rat fetuses in culture, at concentrations ranging from 4 × 10-10 M (Kd of E2 for the estrogen receptors [ER]: 1-4 × 10-10 M) to 4 × 10-6 M (concentration previously shown in the literature to affect in vitro gonocyte proliferation). Exposure to DES and E2 decreased gonocyte number, the effects of DES being much more drastic than those of E2 . Gonocyte number decreased in a concentration-dependent manner (day 3: -5%, -16%, and -80% at 4 × 10-10 M, 4 × 10-8 M, and 4 × 10-6 M of DES, respectively), as well as in a time-dependent manner (at 4 × 10-6 M DES: -31% on day 1, -60% on day 2, and -80% on day 3). This was due to a decrease in the gonocyte mitotic index and a dramatic increase in apoptosis. Importantly, in the presence of the anti-estrogen ICI 182.780 (ICI), the effect of DES was abolished. Sertoli cell number subsequently decreased (day 3), although the rate of apoptosis did not increase. These changes were less dramatic than those observed with gonocytes and were due to a decrease in Sertoli cell proliferation, which was not antagonized by ICI. Addition of 4 × 10-6 M DES had no effect on basal Sertoli cell cyclic adenosine 5′-monophosphate (cAMP) levels or on follicle-stimulating hormone (FSH)-stimulated cAMP production after adjustment for Sertoli cell number. Finally, estrogens reduced both Leydig cell number (-26% on day 3, 4 × 10-6 M DES) and basal and luteinizing hormone (LH)-stimulated testosterone production. The latter effects were antagonized by ICI. In conclusion: 1) E2 and DES induce alterations in the germ line and in somatic cells; 2) gonocyte alteration was the first event detected, and the action of estrogens at this level was mediated by ER, as is the case in Leydig cells; and 3) these data should help us to understand estrogen effects on the fetus and should be considered in the context of the debate on environmental estrogens. [ABSTRACT FROM AUTHOR]- Published
- 2003
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27. In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis.
- Author
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Matos-Rodrigues G, Barroca V, Muhammad AA, Dardillac E, Allouch A, Koundrioukoff S, Lewandowski D, Despras E, Guirouilh-Barbat J, Frappart L, Kannouche P, Dupaigne P, Le Cam E, Perfettini JL, Romeo PH, Debatisse M, Jasin M, Livera G, Martini E, and Lopez BS
- Subjects
- Animals, Mice, Aging genetics, Carcinogenesis genetics, Cell Transformation, Neoplastic, DNA Damage, DNA Repair, Homologous Recombination, Neoplasms, Rad51 Recombinase genetics, Rad51 Recombinase metabolism
- Abstract
Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of the pivotal HR factor RAD51 on cancer development remains puzzling. Particularly, no RAD51 mouse models are available to address the role of RAD51 in aging and carcinogenesis in vivo. We engineered a mouse model with an inducible dominant-negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative mutagenic repair pathways. We found that in vivo expression of SMRad51 led to replicative stress, systemic inflammation, progenitor exhaustion, premature aging and reduced lifespan, but did not trigger tumorigenesis. Expressing SMRAD51 in a breast cancer predisposition mouse model (PyMT) decreased the number and the size of tumors, revealing an anti-tumor activity of SMRAD51. We propose that these in vivo phenotypes result from chronic endogenous replication stress caused by HR decrease, which preferentially targets progenitors and tumor cells. Our work underlines the importance of RAD51 activity for progenitor cell homeostasis, preventing aging and more generally for the balance between cancer and aging., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2023
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28. Foetal exposure to the bisphenols BADGE and BPAF impairs meiosis through DNA oxidation in mouse ovaries.
- Author
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Abdallah S, Jampy A, Moison D, Wieckowski M, Messiaen S, Martini E, Campalans A, Radicella JP, Rouiller-Fabre V, Livera G, and Guerquin MJ
- Subjects
- Female, Mice, Animals, Benzhydryl Compounds toxicity, DNA, Aneuploidy, Meiosis, Ovary
- Abstract
Many endocrine disruptors have been proven to impair the meiotic process which is required for the production of healthy gametes. Bisphenol A is emblematic of such disruptors, as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing use of BPA alternatives raises concerns for public health. Here, we investigated the effects of foetal exposure to two BPA alternatives, bisphenol A Diglycidyl Ether (BADGE) and bisphenol AF (BPAF), on oogenesis in mice. These compounds delay meiosis initiation, increase the number of MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by changes in gene expression in foetal premeiotic germ cells and aberrant mRNA splicing of meiotic genes. We observed an increase in DNA oxidation after exposure to BPA alternatives. Specific induction of oxidative DNA damage during foetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-oxoguanine DNA Glycosylase (OGG1)-deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damage. The supplementation of BPA alternatives with N-acetylcysteine (NAC) counteracts the effects of bisphenols on meiosis. Together, our results propose oxidative DNA lesion as an event that negatively impacts female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for numerous environmental pro-oxidant pollutants, and its discovery, could lead to reconsider the adverse effect of bisphenol mixtures that are simultaneously present in our environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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29. Sorting and Manipulation of Human PGC-LC Using PDPN and Hanging Drop Cultures.
- Author
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Arkoun B, Moison P, Guerquin MJ, Messiaen S, Moison D, Tourpin S, Monville C, and Livera G
- Subjects
- Female, Humans, Mice, Animals, Cell Differentiation, Cell Line, Oocytes, Membrane Glycoproteins metabolism, Germ Cells metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
The generation of oocytes from induced pluripotent stem cells (iPSCs) was proven efficient with mouse cells. However, no human iPSCs have yet been reported to generate cells able to complete oogenesis. Additionally, efficient sorting of human Primordial Germ Cell- like Cells (hPGC-LCs) without genomic integration of fluorescent reporter for their downstream manipulation is still lacking. Here, we aimed to develop a model that allows human germ cell differentiation in vitro in order to study the developing human germline. The hPGC-LCs specified from two iPS cell lines were sorted and manipulated using the PDPN surface marker without genetic modification. hPGC-LCs obtained remain arrested at early stages of maturation and no further differentiation nor meiotic onset occurred when these were cultured with human or mouse fetal ovarian somatic cells. However, when cultured independently of somatic ovarian cells, using BMP4 and the hanging drop-transferred EBs system, early hPGC-LCs further differentiate efficiently and express late PGC (DDX4) and meiotic gene markers, although no SYCP3 protein was detected. Altogether, we characterized a tool to sort hPGC-LCs and an efficient in vitro differentiation system to obtain pre-meiotic germ cell- like cells without using a gonadal niche.
- Published
- 2022
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30. iPSCs derived from infertile men carrying complex genetic abnormalities can generate primordial germ-like cells.
- Author
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Mouka A, Arkoun B, Moison P, Drévillon L, Jarray R, Brisset S, Mayeur A, Bouligand J, Boland-Auge A, Deleuze JF, Yates F, Lemonnier T, Callier P, Duffourd Y, Nitschke P, Ollivier E, Bourdin A, De Vos J, Livera G, Tachdjian G, Maouche-Chrétien L, and Tosca L
- Subjects
- Cell Differentiation genetics, Erythroblasts, Germ Cells metabolism, Humans, Male, Azoospermia genetics, Azoospermia metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies., (© 2022. The Author(s).)
- Published
- 2022
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31. Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.
- Author
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McGlacken-Byrne SM, Del Valle I, Quesne Stabej PL, Bellutti L, Garcia-Alonso L, Ocaka LA, Ishida M, Suntharalingham JP, Gagunashvili A, Ogunbiyi OK, Mistry T, Buonocore F, Crespo B, Moreno N, Niola P, Brooks T, Brain CE, Dattani MT, Kelberman D, Vento-Tormo R, Lagos CF, Livera G, Conway GS, and Achermann JC
- Subjects
- Adenosine analogs & derivatives, Adenosine genetics, Adenosine metabolism, Female, Humans, Meiosis, Primary Ovarian Insufficiency genetics, RNA Helicases genetics
- Abstract
Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.
- Published
- 2022
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32. CEP250 is Required for Maintaining Centrosome Cohesion in the Germline and Fertility in Male Mice.
- Author
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Floriot S, Bellutti L, Castille J, Moison P, Messiaen S, Passet B, Boulanger L, Boukadiri A, Tourpin S, Beauvallet C, Vilotte M, Riviere J, Péchoux C, Bertaud M, Vilotte JL, and Livera G
- Abstract
Male gametogenesis involves both mitotic divisions to amplify germ cell progenitors that gradually differentiate and meiotic divisions. Centrosomal regulation is essential for both types of divisions, with centrioles remaining tightly paired during the interphase. Here, we generated and characterized the phenotype of mutant mice devoid of Cep250/C-Nap1 , a gene encoding for a docking protein for fibers linking centrioles, and characterized their phenotype. The Cep250
-/- mice presented with no major defects, apart from male infertility due to a reduction in the spermatogonial pool and the meiotic blockade. Spermatogonial stem cells expressing Zbtb16 were not affected, whereas the differentiating spermatogonia were vastly lost. These cells displayed abnormal γ H2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ -tubulin foci being separated whereas these were closely associated in wild-type cells. Interestingly, this lack of cohesion was also observed in wild-type female meiocytes, likely explaining the normal fertility of Cep250-/- female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Floriot, Bellutti, Castille, Moison, Messiaen, Passet, Boulanger, Boukadiri, Tourpin, Beauvallet, Vilotte, Riviere, Péchoux, Bertaud, Vilotte and Livera.)- Published
- 2022
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33. Mouse model of radiation-induced premature ovarian insufficiency reveals compromised oocyte quality: implications for fertility preservation.
- Author
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Puy V, Barroca V, Messiaen S, Ménard V, Torres C, Devanand C, Moison D, Lewandowski D, Guerquin MJ, Martini E, Frydman N, and Livera G
- Subjects
- Abortion, Spontaneous, Aneuploidy, Animals, DNA radiation effects, DNA Damage, Disease Models, Animal, Dose-Response Relationship, Radiation, Female, Gamma Rays, Mice, Mice, Inbred C57BL, Ovarian Follicle radiation effects, Ovarian Reserve radiation effects, Sexual Maturation radiation effects, Whole-Body Irradiation, X-Rays, Fertility Preservation methods, Oocytes physiology, Oocytes radiation effects, Ovary radiation effects, Primary Ovarian Insufficiency etiology
- Abstract
Research Question: What is the impact of radiation exposure on oocyte quality and female fertility?, Design: Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined., Results: Radiation exposure induced a massive loss of primordial follicles with LD
50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035)., Conclusions: The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)- Published
- 2021
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34. Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice.
- Author
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Wieckowski M, Ranga S, Moison D, Messiaen S, Abdallah S, Granon S, Habert R, Rouiller-Fabre V, Livera G, and Guerquin MJ
- Subjects
- Animals, Female, HeLa Cells, Humans, Leydig Cells pathology, Male, Mice, Pregnancy, Prenatal Exposure Delayed Effects pathology, Radiation Injuries, Experimental pathology, Benzhydryl Compounds toxicity, Gamma Rays adverse effects, Leydig Cells metabolism, Phenols toxicity, Prenatal Exposure Delayed Effects metabolism, Radiation Injuries, Experimental metabolism
- Abstract
For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions.
- Published
- 2021
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35. The meiosis-specific MEIOB-SPATA22 complex cooperates with RPA to form a compacted mixed MEIOB/SPATA22/RPA/ssDNA complex.
- Author
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Ribeiro J, Dupaigne P, Petrillo C, Ducrot C, Duquenne C, Veaute X, Saintomé C, Busso D, Guerois R, Martini E, and Livera G
- Subjects
- Animals, Cell Line, Tumor, HEK293 Cells, Homologous Recombination, Humans, Meiosis, Mice, Models, Molecular, Multiprotein Complexes, Protein Conformation, Cell Cycle Proteins metabolism, Chromosome Pairing, Crossing Over, Genetic, DNA, Single-Stranded metabolism, DNA-Binding Proteins metabolism, Replication Protein A metabolism
- Abstract
During meiosis, programmed double-strand breaks are repaired by homologous recombination (HR) to form crossovers that are essential to homologous chromosome segregation. Single-stranded DNA (ssDNA) containing intermediates are key features of HR, which must be highly regulated. RPA, the ubiquitous ssDNA binding complex, was thought to play similar roles during mitotic and meiotic HR until the recent discovery of MEIOB and its partner, SPATA22, two essential meiosis-specific proteins. Here, we show that like MEIOB, SPATA22 resembles RPA subunits and binds ssDNA. We studied the physical and functional interactions existing between MEIOB, SPATA22, and RPA, and show that MEIOB and SPATA22 interact with the preformed RPA complex through their interacting domain and condense RPA-coated ssDNA in vitro. In meiotic cells, we show that MEIOB and SPATA22 modify the immunodetection of the two large subunits of RPA. Given these results, we propose that MEIOB-SPATA22 and RPA form a functional ssDNA-interacting complex to satisfy meiotic HR requirements by providing specific properties to the ssDNA., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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36. Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis.
- Author
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Wang M, Yang Y, Cansever D, Wang Y, Kantores C, Messiaen S, Moison D, Livera G, Chakarov S, Weinberger T, Stremmel C, Fijak M, Klein B, Pleuger C, Lian Z, Ma W, Liu Q, Klee K, Händler K, Ulas T, Schlitzer A, Schultze JL, Becher B, Greter M, Liu Z, Ginhoux F, Epelman S, Schulz C, Meinhardt A, and Bhushan S
- Subjects
- Animals, Cell Differentiation, Cell Lineage, Epididymis immunology, Epididymis metabolism, Infertility, Male metabolism, Infertility, Male physiopathology, Male, Mice, Mice, Inbred C57BL, Monocytes immunology, Testis immunology, Testis metabolism, Infertility, Male immunology, Macrophages immunology, Macrophages metabolism
- Abstract
Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64
hi MHCIIlo and CD64lo MHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs., Competing Interests: The authors declare no competing interest.- Published
- 2021
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37. The Role of ERα36 in Development and Tumor Malignancy.
- Author
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Thiebaut C, Konan HP, Guerquin MJ, Chesnel A, Livera G, Le Romancer M, and Dumond H
- Subjects
- Animals, Breast Neoplasms genetics, Drug Resistance, Neoplasm, Estrogen Receptor alpha genetics, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Animal growth & development, Neoplasms metabolism, Neoplasms, Germ Cell and Embryonal genetics, Testicular Neoplasms genetics, Estrogen Receptor alpha physiology, Neoplasms genetics
- Abstract
Estrogen nuclear receptors, represented by the canonical forms ERα66 and ERβ1, are the main mediators of the estrogen-dependent pathophysiology in mammals. However, numerous isoforms have been identified, stimulating unconventional estrogen response pathways leading to complex cellular and tissue responses. The estrogen receptor variant, ERα36, was cloned in 2005 and is mainly described in the literature to be involved in the progression of mammary tumors and in the acquired resistance to anti-estrogen drugs, such as tamoxifen. In this review, we will first specify the place that ERα36 currently occupies within the diversity of nuclear and membrane estrogen receptors. We will then report recent data on the impact of ERα36 expression and/or activity in normal breast and testicular cells, but also in different types of tumors including mammary tumors, highlighting why ERα36 can now be considered as a marker of malignancy. Finally, we will explain how studying the regulation of ERα36 expression could provide new clues to counteract resistance to cancer treatments in hormone-sensitive tumors.
- Published
- 2020
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38. Homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait.
- Author
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Caburet S, Heddar A, Dardillac E, Creux H, Lambert M, Messiaen S, Tourpin S, Livera G, Lopez BS, and Misrahi M
- Abstract
Background: Primary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic BRCA2 truncated variants has been reported. Here, we report a novel phenotype of isolated POI with a BRCA2 variant in a consanguineous Turkish family., Methods: Exome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of BRCA2 in human foetal ovaries was studied., Results: ES identified a homozygous missense c.8524C>T/p.R2842C -BRCA2 variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient's cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs., Conclusion: We describe the functional assessment of a homozygous hypomorphic BRCA2 variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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39. shani mutation in mouse affects splicing of Spata22 and leads to impaired meiotic recombination.
- Author
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Petrillo C, Barroca V, Ribeiro J, Lailler N, Livera G, Keeney S, Martini E, and Jain D
- Subjects
- Alleles, Amino Acid Sequence, Animals, Base Sequence, Breeding, Connectome, Female, Gametogenesis genetics, Homozygote, Male, Mice, Mice, Transgenic, Pedigree, Spermatocytes cytology, Spermatocytes metabolism, Cell Cycle Proteins genetics, Homologous Recombination, Meiosis genetics, Mutation
- Abstract
Recombination is crucial for chromosome pairing and segregation during meiosis. SPATA22, along with its direct binding partner and functional collaborator, MEIOB, is essential for the proper repair of double-strand breaks (DSBs) during meiotic recombination. Here, we describe a novel point-mutated allele (shani) of mouse Spata22 that we isolated in a forward genetic screen. shani mutant mice phenocopy Spata22-null and Meiob-null mice: mutant cells appear to form DSBs and initiate meiotic recombination, but are unable to complete DSB repair, leading to meiotic prophase arrest, apoptosis and sterility. shani mutants show precocious loss of DMC1 foci and improper accumulation of BLM-positive recombination foci, reinforcing the requirement of SPATA22-MEIOB for the proper progression of meiotic recombination events. The shani mutation lies within a Spata22 coding exon and molecular characterization shows that it leads to incorrect splicing of the Spata22 mRNA, ultimately resulting in no detectable SPATA22 protein. We propose that the shani mutation alters an exonic splicing enhancer element (ESE) within the Spata22 transcript. The affected DNA nucleotide is conserved in most tetrapods examined, suggesting that the splicing regulation we describe here may be a conserved feature of Spata22 regulation.
- Published
- 2020
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40. The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells.
- Author
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Zhang J, Gurusaran M, Fujiwara Y, Zhang K, Echbarthi M, Vorontsov E, Guo R, Pendlebury DF, Alam I, Livera G, Emmanuelle M, Wang PJ, Nandakumar J, Davies OR, and Shibuya H
- Subjects
- Alleles, Animals, Cell Line, Tumor, Chromosome Pairing, DNA Breaks, Double-Stranded, Male, Mice, Inbred C57BL, Protein Binding, Protein Stability, Spermatozoa metabolism, BRCA2 Protein metabolism, Homologous Recombination genetics, Meiosis genetics, Mitosis genetics, Multiprotein Complexes metabolism, Neoplasms genetics, Rad51 Recombinase metabolism
- Abstract
Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1
-/- ) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1-/- reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.- Published
- 2020
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41. Author Correction: Maternal vitamin C regulates reprogramming of DNA methylation and germline development.
- Author
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DiTroia SP, Percharde M, Guerquin MJ, Wall E, Collignon E, Ebata KT, Mesh K, Mahesula S, Agathocleous M, Laird DJ, Livera G, and Ramalho-Santos M
- Abstract
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2019
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42. Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads.
- Author
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Bellutti L, Abby E, Tourpin S, Messiaen S, Moison D, Trautmann E, Guerquin MJ, Rouiller-Fabre V, Habert R, and Livera G
- Subjects
- Animals, Cell Line, Cell Proliferation, Gonads cytology, HEK293 Cells, Humans, Mice, Mice, Inbred Strains, Mice, Mutant Strains, Receptors, Retinoic Acid metabolism, Testosterone analysis, Testosterone biosynthesis, Gonads metabolism, Retinoic Acid 4-Hydroxylase metabolism, Tretinoin metabolism
- Abstract
In female mammals, germ cells enter meiosis in the fetal ovaries, while in males, meiosis is prevented until postnatal development. Retinoic acid (RA) is considered the main inducer of meiotic entry, as it stimulates Stra8 which is required for the mitotic/meiotic switch. In fetal testes, the RA-degrading enzyme CYP26B1 prevents meiosis initiation. However, the role of endogenous RA in female meiosis entry has never been demonstrated in vivo. In this study, we demonstrate that some effects of RA in mouse fetal gonads are not recapitulated by the invalidation or up-regulation of CYP26B1. In organ culture of fetal testes, RA stimulates testosterone production and inhibits Sertoli cell proliferation. In the ovaries, short-term inhibition of RA-signaling does not decrease Stra8 expression. We develop a gain-of-function model to express CYP26A1 or CYP26B1. Only CYP26B1 fully prevents STRA8 induction in female germ cells, confirming its role as part of the meiotic prevention machinery. CYP26A1, a very potent RA degrading enzyme, does not impair the formation of STRA8-positive cells, but decreases Stra8 transcription. Collectively, our data reveal that CYP26B1 has other activities apart from metabolizing RA in fetal gonads and suggest a role of endogenous RA in amplifying Stra8, rather than being the initial inducer of Stra8. These findings should reactivate the quest to identify meiotic preventing or inducing substances.
- Published
- 2019
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43. Maternal vitamin C regulates reprogramming of DNA methylation and germline development.
- Author
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DiTroia SP, Percharde M, Guerquin MJ, Wall E, Collignon E, Ebata KT, Mesh K, Mahesula S, Agathocleous M, Laird DJ, Livera G, and Ramalho-Santos M
- Subjects
- Animals, Ascorbic Acid Deficiency physiopathology, Cell Count, DNA-Binding Proteins genetics, Epigenomics, Female, Loss of Function Mutation, Meiosis physiology, Mice, Models, Animal, Pregnancy, Proto-Oncogene Proteins genetics, Ascorbic Acid metabolism, DNA Methylation physiology, Germ Cells physiology, Transcriptome physiology
- Abstract
Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals
1,2 . The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3-7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8-10 . TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11-15 . Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.- Published
- 2019
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44. A truncating MEIOB mutation responsible for familial primary ovarian insufficiency abolishes its interaction with its partner SPATA22 and their recruitment to DNA double-strand breaks.
- Author
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Caburet S, Todeschini AL, Petrillo C, Martini E, Farran ND, Legois B, Livera G, Younis JS, Shalev S, and Veitia RA
- Subjects
- Adolescent, Adult, Animals, Biomarkers, Cell Line, Consanguinity, Female, Gene Expression, Humans, Informatics methods, Mice, Pedigree, Primary Ovarian Insufficiency diagnosis, Protein Binding, Exome Sequencing, Young Adult, Cell Cycle Proteins metabolism, DNA Breaks, Double-Stranded, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Mutation, Primary Ovarian Insufficiency etiology, Primary Ovarian Insufficiency metabolism
- Abstract
Background: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1-3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic., Methods: We performed exome sequencing (WES) of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB)., Findings: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs., Interpretation: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob
-/- mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB) responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. FUND: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
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45. Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency.
- Author
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Huhtaniemi I, Hovatta O, La Marca A, Livera G, Monniaux D, Persani L, Heddar A, Jarzabek K, Laisk-Podar T, Salumets A, Tapanainen JS, Veitia RA, Visser JA, Wieacker P, Wolczynski S, and Misrahi M
- Subjects
- Adult, Female, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Mutation genetics, Primary Ovarian Insufficiency genetics
- Abstract
Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2018
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46. Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis.
- Author
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Eladak S, Moison D, Guerquin MJ, Matilionyte G, Kilcoyne K, N'Tumba-Byn T, Messiaen S, Deceuninck Y, Pozzi-Gaudin S, Benachi A, Livera G, Antignac JP, Mitchell R, Rouiller-Fabre V, and Habert R
- Subjects
- Animals, Female, Heterografts, Humans, Male, Mice, Mice, Nude, Pregnancy, Pregnancy Trimester, First, Pregnancy Trimester, Second, Radioimmunoassay, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Testis cytology, Testis embryology, Testosterone blood, Benzhydryl Compounds toxicity, Environmental Pollutants toxicity, Leydig Cells drug effects, Phenols toxicity, Spermatozoa drug effects, Testis drug effects
- Abstract
Background: Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 μM BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models., Methods: Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 μM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 μM BPA (~ 500 μg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 μM and 0.038 μM respectively. Mice grafted with second trimester testes received 0.5 and 50 μg/kg/day BPA by oral gavage for 5 weeks., Results: With first trimester human testes, using the hFeTA model, 10 μM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2γ, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice., Conclusions: Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures.
- Published
- 2018
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47. [In vitro oogenesis: How far have we come?]
- Author
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Arkoun B and Livera G
- Subjects
- Animals, Cell Differentiation, Fetal Development, Humans, Mice, Oogenesis genetics, Pluripotent Stem Cells, Oogenesis physiology
- Abstract
Oogenesis is a complex cellular and molecular process whose fundamental mechanisms are still poorly described or not yet elucidated, especially in human species. The development of an in vitro model of oogenesis, particularly during fetal development in humans, is a critical step that would allow: (i) a better understand of the biological mechanisms of oogenesis; (ii) a refinement of medical diagnosis for women suffering from infertility; and (iii) providing new therapeutics for reproductive pathologies. The genesis of this model could be considered from ES/iPS cells. In this article, we will trace the physiological mechanisms of oogenesis in vivo and discuss the studies carried out in the field of in vitro oogenesis from ES/iPS cells, as well as the challenges to be met in the future., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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48. A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.
- Author
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Fouquet B, Pawlikowska P, Caburet S, Guigon C, Mäkinen M, Tanner L, Hietala M, Urbanska K, Bellutti L, Legois B, Bessieres B, Gougeon A, Benachi A, Livera G, Rosselli F, Veitia RA, and Misrahi M
- Subjects
- Adult, Chromosome Aberrations, Fanconi Anemia Complementation Group D2 Protein genetics, Fanconi Anemia Complementation Group D2 Protein metabolism, Female, Genetic Predisposition to Disease, Genotype, Homologous Recombination, Humans, Male, Middle Aged, Pedigree, Phenotype, Primary Ovarian Insufficiency pathology, Ubiquitination, Exome Sequencing, Young Adult, DNA Helicases genetics, Homozygote, Mutation, Ovary physiopathology, Primary Ovarian Insufficiency genetics
- Abstract
Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm
-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.- Published
- 2017
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49. Human foetal ovary shares meiotic preventing factors with the developing testis.
- Author
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Frydman N, Poulain M, Arkoun B, Duquenne C, Tourpin S, Messiaen S, Habert R, Rouiller-Fabre V, Benachi A, and Livera G
- Subjects
- Animals, Cell Proliferation physiology, Female, Humans, Male, Mice, Oogonia cytology, Oogonia metabolism, Ovary metabolism, Signal Transduction physiology, Spermatogonia cytology, Spermatogonia metabolism, Testis metabolism, Embryonic Germ Cells metabolism, Meiosis physiology, Ovary embryology, Testis embryology
- Abstract
Study Question: How can pre-meiotic germ cells persist in the human foetal ovary?, Summary Answer: Numerous oogonia escaping meiotic entry were retrieved throughout human ovarian development simultaneously with the expression of signalling pathways preventing meiosis, typically described in the rodent embryonic testis., What Is Known Already: The transition from mitosis to meiosis is a key event in female germ cells that remains poorly documented in research on the human ovary. Previous reports described a strikingly asynchronous differentiation in the human female germ line during development, with the persistence of oogonia among oocytes and follicles during the second and third trimesters. The possible mechanisms allowing some cells to escape meiosis remain elusive., Study Design Size, Duration: In order to document the extent of this phenomenon, we detailed the expression profile of germ cell differentiation markers using 73 ovaries ranging from 6.4 to 35 weeks post-fertilization., Participants/materials Setting, Methods: Pre-meiotic markers were detected by immunohistochemistry or qRT-PCR. The expression of the main meiosis-preventing factors identified in mice was analysed, and their functionality assessed using organ cultures., Main Results and the Role of Chance: Oogonia stained for AP2γ could be traced from the first trimester until the end of the third trimester. Female germ cell differentiation is organized both in time and space in a centripetal manner in the foetal human ovary. Unexpectedly, some features usually ascribed to rodent pre-spermatogonia could be observed in human foetal ovaries, such as NANOS2 expression and quiescence in some germ cells. The two main somatic signals known to inhibit meiosis in the mouse embryonic testis, CYP26B1 and FGF9, were detected in the human ovary and act simultaneously to repress STRA8 and meiosis in human foetal female germ cells., Large Scale Data: N/A., Limitations Reason for Caution: Our conclusions relied partly on in vitro experiments. Germ cells were not systematically identified with immunostaining and some may have thus escaped analysis., Wider Implications of the Findings: We found evidence that a robust repression of meiotic entry is taking place in the human foetal ovary, possibly explaining the exceptional long-lasting presence of pre-meiotic germ cells until late gestational age. This result calls for a redefinition of the markers known as classical male markers, which may in fact characterize mammalian developing gonads irrespectively of their sex., Study Funding/competing Interest(s): This research was supported by the Université Paris Diderot-Paris 7 and Université Paris-Sud, CEA, INSERM, and Agence de la Biomédecine. The authors declare no conflict of interest., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2017
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50. Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53-dependent and results in female sterility.
- Author
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Livera G, Uzbekov R, Jarrier P, Fouchécourt S, Duquenne C, Parent AS, Marine JC, and Monget P
- Subjects
- Animals, Anti-Mullerian Hormone metabolism, Female, Follicle Stimulating Hormone, Infertility, Female pathology, Mice, Mice, Knockout, Oocytes metabolism, Oocytes pathology, Ovarian Follicle metabolism, Ovarian Follicle pathology, Ovary growth & development, Ovary metabolism, Ovary pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism, Infertility, Female genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-mdm2 genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Murine double minute 2 and 4 (Mdm2, Mdm4) are major p53-negative regulators, preventing thus uncontrolled apoptosis induction in numerous cell types, although their function in the female germ line has received little attention. In the present work, we have generated mice with specific invalidation of Mdm2 and Mdm4 genes in the mouse oocyte (Mdm2(Ocko) and Mdm4(Ocko) mice), to test their implication in survival of these germ cells. Most of the Mdm2(Ocko) but not Mdm4(Ocko) mice were sterile, with a dramatic reduction of the weight of ovaries and genital tract, a strong increase in follicle-stimulating hormone and luteinizing hormone serum levels, and a reduction of anti-mullerian hormone serum levels. Histological analyses revealed an obvious decrease of the number of growing follicles beyond the primary stage in Mdm2(Ocko) ovaries in comparison to controls, with a pronounced increase in the apparition of primary atretic follicles, most being devoid of oocyte. Similar phenotypes were observed with Mdm2(Ocko) Mdm4(Ocko) ovaries, with no worsening of the phenotype. However, we failed to detect any increase in p53 level in mutant oocytes, nor any other apoptotic marker, introgression of this targeted invalidation in p53-/- mice restored the fertility of females. This study is the first to show that Mdm2, but not Mdm4, has a critical role in oocyte survival and would be involved in premature ovarian insufficiency phenotype., (© 2016 Federation of European Biochemical Societies.)
- Published
- 2016
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