Two redundant transcription factor binding sites in a single enhancer are essential for mammalian sex determination
Meshi Ridnik , Elisheva Abberbock, Veronica Alipov, Shelly Ziv Lhermann, Shoham Kaufman, Maor Lubman, Francis Poulat, Nitzan Gonen
Development and Pathology of the gonad
Genetics, cell biology and development
In mammals, the chromosomal sex (XX or XY) is established at fertilization. However, the undifferentiated embryonic gonad, or genital crest, remains bipotential until the stage of gonadal determination, at which point it differentiates into either an ovary or a testis.
This event occurs at approximately eleven days of embryonic life in mice and at approximately five weeks of gestation in humans.
The choice between the testicular and ovarian pathways is made in undifferentiated precursors of the genital crest, which differentiate into supporting cells: the testicular Sertoli cells or the ovarian pre-granulosa cells.
In XY gonads, the expression of SRY, which is carried by the Y chromosome, activates the SOX9 gene, which controls Sertoli cell differentiation.
In XX gonads, the -KTS splice variant of WT1 associated with the WNT4/RSPO1 pathway leads to expression of the transcription factor FOXL2, which controls pre-granulosa cell differentiation.
Following their determination, the supporting cells orchestrate the development of the gonads, resulting in functional organs that produce sex hormones and gametes after puberty. Any disruption to these processes can result in disorders of sexual development, often associated with infertility, which can in turn lead to complete sex reversal.
Furthermore, supporting cells play a crucial role in maintaining the sexual identity of adult gonads. Our recent research has revealed that targeted deletion of the Trim28 gene in ovarian somatic cells induces their post-natal reprogramming into testicular cells. The process entails the trans-differentiation of granulosa cells into Sertoli cells, which ultimately leads to postnatal gonadal sex reversal.
In addition to studying testicular and ovarian determination processes, our group uses murine genetics to elucidate the mechanisms of differentiation and maintenance of the adult sexual phenotype. To this end, we use histological, transcriptomic, genomic and biochemical approaches to study our mouse models.
Publications of the team
Transposable elements acquire time-and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development
Isabelle Stevant Nitzan Gonen Francis Poulat
Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally
Pascal Philibert, Stéphanie Déjardin, Mélissa Girard, Quentin Durix, Anne-Alicia Gonzalez, Xavier Mialhe, Mathieu Tardat, Francis Poulat, Brigitte Boizet-Bonhoure
TRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Moïra Rossitto , Stephanie Déjardin , Chris M Rands , Stephanie Le Gras , Roberta Migale , Mahmoud-Reza Rafiee , Yasmine Neirijnck , Alain Pruvost , Anvi Laetitia Nguyen , Guillaume Bossis , Florence Cammas , Lionel Le Gallic , Dagmar Wilhelm , Robin Lovell-Badge , Brigitte Boizet-Bonhoure , Serge Nef , Francis Poulat
Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health
B. Boizet-Bonhoure, S. Dejardin, M. Rossitto, F. Poulat and P. Philibert
In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice
Rossitto M, Ollivier M, Déjardin S, Pruvost A, Brun C, Marchive C, Nguyen AL, Ghettas A, Keime C, de Massy B, Poulat F, Philibert P, Boizet-Bonhoure B
The Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism.
Weger BD, Gobet C, Yeung J, Martin E, Jimenez S, Betrisey B, Foata F, Berger B, Balvay A, Foussier A, Charpagne A, Boizet-Bonhoure B, Chou CJ, Naef F, Gachon F
Microtubule polyglutamylation and acetylation drive microtubule dynamics critical for platelet formation.
van Dijk J, Bompard G, Cau J, Kunishima S, Rabeharivelo G, Mateos-Langerak J, Cazevieille C, Cavelier P, Boizet-Bonhoure B, Delsert C, Morin N
Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen.
Rossitto M, Marchive C, Pruvost A, Sellem E, Ghettas A, Badiou S, Sutra T, Poulat F, Philibert P, Boizet-Bonhoure B
Sex reversal following deletion of a single distal enhancer of Sox9.
Gonen N, Futtner CR, Wood S, Garcia-Moreno SA, Salamone IM, Samson SC, Sekido R, Poulat F, Maatouk DM, Lovell-Badge R
A role for SOX9 in post-transcriptional processes: insights from the amphibian oocyte.
Penrad-Mobayed M, Perrin C, L'Hôte D, Contremoulins V, Lepesant JA, Boizet-Bonhoure B, Poulat F, Baudin X, Veitia RA
In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures
Rahmoun M, Lavery R, Laurent-Chaballier S, Bellora N, Philip GK, Rossitto M, Symon A, Pailhoux E, Cammas F, Chung J, Bagheri-Fam S, Murphy M, Bardwell V, Zarkower D, Boizet-Bonhoure B, Clair P, Harley VR, Poulat F.
Development and pathology of the gonad
Boizet-Bonhoure, B.
Molecular events and signalling pathways of male germ cell differentiation in mouse
Rossitto M, Philibert P, Poulat F, Boizet-Bonhoure B.
The multiples roles of the Prostaglandin D2 signaling pathway in reproduction
Rossitto M, Ujjan S, Poulat F, Boizet-Bonhoure B
Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination
Trimarco A, Forese MG, Alfieri V, Lucente A, Brambilla P, Dina G, Pieragostino D, Sacchetta P, Urade Y, Boizet-Bonhoure B, Boneschi FM, Quattrini A, Taveggia C.
Anatomical and Molecular Analyses of XY Ovaries from the African Pygmy Mouse Mus minutoides
Rahmoun M, Perez J, Saunders PA, Boizet-Bonhoure B, Wilhelm D, Poulat F, Veyrunes F.
Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis
Moniot B, Ujjan S, Champagne J, Hirai H, Aritake K, Nagata K, Dubois E, Nidelet S, Nakamura M, Urade Y, Poulat F, Boizet-Bonhoure B
Unilateral Cryptorchidism in Mice Mutant for Ptgds
Philibert P, Boizet-Bonhoure B, Bashamboo A, Paris F, Aritake K, Urade Y, Leger J, Sultan C, Poulat F.
The Impressionistic Landscape of Meiotic Recombination
Lichten, M., de Massy, B.
Hematopoietic prostaglandin D synthase (H-Pgds) is expressed in the early embryonic gonad and participates to the initial nuclear translocation of the SOX9 protein
Moniot B, Farhat A, Aritake K, Declosmenil F, Nef S, Eguchi N, Urade Y, Poulat F, Boizet-Bonhoure B.
Inhibition of SRY-Calmodulin Complex Formation Induces Ectopic Expression of Ovarian Cell Markers in Developing XY Gonads.
Sim H, Argentaro A, Czech DP, Bagheri-Fam S, Sinclair AH, Koopman P, Boizet-Bonhoure B, Poulat F, Harley VR
Temporal and spatial SOX9 expression patterns in the course of gonad development of the caudate amphibian Pleurodeles waltl.
Dumond, H., Al-Asaad, I., Chesnel, A., Chardard, D., Boizet-Bonhoure, B., Flament, S., Kuntz, S.
Hematopoietic-Prostaglandin D2 synthase through PGD2 production is involved in the adult ovarian physiology
Farhat A, Philibert P, Sultan C, Poulat F, Boizet-Bonhoure B.
MiniSOX9, a dominant-negative variant in colon cancer cells
Abdel-Samad R, Zalzali H, Rammah C, Giraud J, Naudin C, Dupasquier S, Poulat F, Boizet-Bonhoure B, Lumbroso S, Mouzat K, Bonnans C, Pignodel C, Raynaud P, Fort P, Quittau-Prévostel C, Blache P
Relationship between glutathione S-transferase P1 polymorphisms and chronic obstructive pulmonary disease in a Tunisian population
Lakhdar R, Denden S, Knani J, Leban N, Daimi H, Hassine M, Lefranc G, Ben Chibani J, Haj Khelil A.
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IMGT® - the international ImMunoGeneTics information system®
Shuttling of SOX proteins
Malki S, Boizet-Bonhoure B, Poulat F
Unusual Virilization in Girls with Juvenile Granulosa Cell Tumors of the Ovary Is Related to Intratumoral Aromatase Deficiency.
Kalfa N, Méduri G, Philibert P, Patte C, Boizet-Bonhoure B, Thibaut E, Pienkowski C, Jaubert F, Misrahi M, Sultan C.
Shuttling of SOX proteins
Malki S, Boizet-Bonhoure B, Poulat F
The new molecular biology of granulosa cell tumors of the ovary.
Kalfa, N., Veitia, RA., Benayoun, BA., Boizet-Bonhoure, B., Sultan, C.
Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation?
Kalfa, N., Philibert, P., Sultan, C
Hypospadias and genetics
Kalfa, N., Philibert, P., Sultan, C.
The PGD2 pathway, independently of FGF9, amplifies SOX9activity in Sertoli cells during male sexual differentiation
Moniot, B., Declosmenil, F, Barrionuevo, F., Scherer, G., Aritake, K., Malki, S., Marzi, M., Cohen-Solal, A., Georg, I., Klattig, J., Englert, C., Kim, Y., Capel, B., Eguchi, N., Urade, Y., Boizet-Bonhoure, B., Poulat, F.
Juvenile granulosa-cell tumor: Clinical and molecular expression.
Kalfa N, Philibert P, Patte C, Thibaud E, Pienkowski C, Ecochard A, Boizet-Bonhoure B, Fellous M, Sultan C.
Male specific expression of Lipocalin-type Prostaglandin D Synthase (cPTGDS) during chicken gonadal differentiation: relationship with cSOX9
Moniot, B., Boizet-Bonhoure, B., Poulat, F.
La Prostaglandine D2: nouveaux rôles dans la gonade embryonnaire et pathologique.
Malki, S., Declosmenil, F., Farhat, A., Moniot, B., Poulat, F., Boizet-Bonhoure, B.
Granulosa cell tumor of the testis in children : evidence of localized intratesticular sex reversal through aberrant expression of FOXL2, an ovary-determining gene.
Kalfa, N., M. Fellous, B. Boizet-Bonhoure, C. Patte, P. Duvillard, C. Pienkowski, F. Jaubert, A. Ecochard and C. Sultan.
Sex-specific expression of SOX9 during gonadogenesis in the amphibian Xenopus tropicalis.
El Jamil, A., Kanhoush, R., Magre, S., Boizet-Bonhoure, B., Penrad-Mobayed, M.
The regulation of Sox9 gene expression by the GATA4/FOG2 transcriptional complex in dominant XX sex reversal mouse models
Manuylov, NL., Fujiwara, Y., Adameyko, II., Poulat, F., Tevosian, SG.
Expression and biological role of the prostaglandin D synthase / SOX9 pathway in Human Ovarian Cancer Cell
Malki, S., Bibeau, F., Notarnicola, C., Roques, S., Berta, P., Poulat, F., Boizet-Bonhoure, B.
Transcription factors involved in pancreas development are expressed in pediatric solid pseudopapillary tumors
Galmiche, L., Sarnacki, S., Verkarre, V., Boizet, B. Duvillie, B., Fabre, M., Jaubert, F
Coexpression of Wilms' tumor suppressor 1 (WT1) and androgen receptor (AR)in the genital tract of human male embryos and regulation of AR promoter activity by WT1
Köhler, B., Delezoide, AL., Boizet-Bonhoure, B., McPhaul, MJ., Sultan, C., Lumbroso, S
Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination.
Kim, Y., Kobayashi, A., Sekido, R., DiNapoli, L., Brennan, J., Chaboissier, M.C., Poulat, F., Behringer, R.R., Lovell-Badge, R. and Capel, B.
Transient expression of SOX9 protein during follicular development in the adult mouse ovary.
Notarnicola C, Malki S, Berta P, Poulat F, Boizet-Bonhoure B.
Transient expression of SOX9 protein during follicular development in the adult mouse ovary.
Notarnicola C, Malki S, Berta P, Poulat F, Boizet-Bonhoure B.
Cytoplasmic retention of the sex-determining factor SOX9 via the microtubule network
Malki, S., Berta, P., Poulat, F., Boizet-Bonhoure, B.
Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation
Malki, S., Nef, S., Notarnicola, C., Thevenet, L., Gasca, S., Méjean, C., Berta, P., Poulat, F., Boizet-Bonhoure, B.
Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development.
Nef, S., Schaad, O., Stallings, N.R., Cederroth, C.R., Pitetti, J.L., Schaer, G., Malki, S., Dubois-Dauphin, M., Boizet-Bonhoure, B., Descombes, P., Parker, K.L. and Vassalli, J.D.
NHERF2/SIP-1 interacts with mouse SRY via a different mechanism than human SRY
Thevenet, L., Albrecht, K.H., Malki, S., Berta, P., Boizet-Bonhoure, B. and Poulat, F.
Regulation of human SRY subcellular distribution by its acetylation/deacetylation.
Thevenet, L., Mejean, C., Moniot, B., Bonneaud, N., Galeotti, N., Aldrian-Herrada, G., Poulat, F., Berta, P., Benkirane, M., Boizet-Bonhoure, B.
SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals.
Moniot, B., Biau, S., Faure, S., Nielsen, C.M., Berta, P., Roberts, D.J. and de Santa Barbara, P.
SOX9 interacts with a component of the human thyroid hormone receptor associated protein complex
Zhou, R., Bonneaud, N., Yuan, C., de Santa Barbara, P., Boizet, B., Schomber, T., Scherer, G., Roeder, G., Poulat, F., Berta, P.
Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis : implications for the developmental anomalies of X chromosomlinkes Kallmann syndrome.
Hardelin, J.P., Julliard, A.K., Moniot, B., Soussi-Yanicostas, N., Verney, C., Schwanzel, M., Ayer-Le-Lièvre, C. and Petit, C.
Thèses et hdr
Impact of in utero exposure to non-steroidal analgesics and anti-inflammatory drugs on early development and maturation of male reproductive organs in mice 09/12/2016
Defended by Moïra Rossitto on 09-12-2016