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    Spermatogenesis & infertility: Gamete Interaction

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    Projects co-leaders

     

    +33 158411171                                                           +33144412320
    jean-philippe.wolf@inserm.fr                                    
    ahmed.ziyyat@inserm.fr

     

    Research Topics:

    A crucial step of fertilization is sperm-egg contact that allows the two gametes to fuse and create a zygote. Many questions remain open about the molecules that bring the gamete’s membranes together. Only four molecules are known to be essential for this step: Izumo1 and Spaca6 on sperm and Cd9 and Juno on the oocyte. The aim of our program is to determine the molecular complex involved in sperm oocyte recognition, adhesion and fusion. Our group is working both on human and mice gametes.

     

    Participants:

    Ahmed Ziyyat, Principal investigator, MCF (Université Paris Descartes)
    Jean-Philippe Wolf, Principal investigator, PU-PH Reproductive Biology (Cochin hospital)

    Amira Sallem, PhD student, Reproductive Biology (Cochin hospital)
    Anne-Lyse Denizot, post-doctoral fellow
    Côme Ialy-Radio, ITA (TS, INSERM)
    Virginie Barraud-Lange, MCU-PH Reproductive Biology (Cochin hospital)
    Sandrine Barbaux (CR1, INSERM)
    Sophie Favier (PhD student)
    Méline Homps-Legrand (M2 student)
    Franck Kouakou (research scientist, Cochin Hospital)
    Audrey L’hostis (AI, Université Paris Descartes)
    Cécile Olivia Violet (M2 student)

     

    Scientific questions

    The importance of membrane/ cytoskeleton attachment is well established but what are providing the molecules to this link during gamete adhesion fusion?
    What are the roles of sperm integrins and immunoglobulins during fertilization?
    By which mechanisms the fertilin cyclic peptide (cFEE or cQDE) increases fertilization?

     

    Recent achievements

    We have shown that Cd9 organizes the oocyte membrane sperm binding molecular complex (Ziyyat et al. J Cell Sci 2006) and generates fusion competent sites on the egg membrane for mammalian fertilization (Jegou et al. Proc Natl Acad Sci USA 2011) and that along with Izumo1 and its receptor Juno, Cd9 concomitantly accumulates in the adhesion area (Chalbi et al. Development 2014).

    Juno belongs to GPI-anchored proteins that associate to lipid rafts; we have demonstrated that cholesterol depletion disorganizes oocyte membrane rafts, altering mouse fertilization. Using siRNA and antibodies inhibition, we have demonstrated the involvement of two other oocyte GPI-APs, Gas1 and Gfra1 in gametes adhesion/ fusion (in press, 2016).
    On the sperm side, we have shown that integrins are functionally involved in the sperm-egg interaction process.

    We have discovered the transfer of oocyte membrane fragments to the fertilizing spermatozoon in the perivitelline space (Barraud-Lange et al. Faseb J 2007). Two mechanisms for this exchange between gametes exist: trogocytosis and exosomes, suggesting that it could be of physiological importance.

    We discovered that a cyclic peptide, mimicking the binding site of ADAM2, increases the fusion ability of mouse and human gametes (Barraud-Lange et al. Fertil Steril 2009). It can be used in human as well as in domestic animals.

     

    Selected publications

    Sallem A, Santulli P, Barraud-Lange V, Le Foll N, Ferreux L, Maignien C, Bourdon M, Chapron C, de Ziegler D, Wolf JP, Pocate-Cheriet K. (2018) Extended culture of poor-quality supernumerary embryos improves ART outcomes.  J Assist Reprod Genet. Feb;35(2):311-319.

    Barbaux S, El Khattabi L, Ziyyat A. (2017) ZP2 heterozygous mutation in an infertile woman. Hum Genet 136:1489-1491

    Agopiantz, M., Xandre-Rodriguez, L., Jin, B., Urbistondoy, G., Ialy-Radio, C., Chalbi, M., Wolf, J. P., Ziyyat, A. and Lefevre, B. (2016). Growth arrest specific 1 (Gas1) and glial cell line-derived neurotrophic factor receptor a1 (Gfra1), two mouse oocyte glycosylphosphatidylinositol-anchored proteins, are involved in fertilisation. Reprod Fertil Dev. 2017 29:824-837

    Ziyyat A, Rubinstein E, Monier-Gavelle F, Barraud V, Kulski O, Prenant M, Boucheix C, Bomsel M, Wolf JP 2006 CD9 controls the formation of clusters that contain tetraspanins and the integrin alpha 6 beta 1, which are involved in human and mouse gamete fusion. J Cell Sci 119:416-424

    Jegou A, Ziyyat A, Barraud-Lange V, Perez E, Wolf JP, Pincet F, Gourier C 2011 CD9 tetraspanin generates fusion competent sites on the egg membrane for mammalian fertilization. Proc Natl Acad Sci U S A 108:10946-10951

    Chalbi M, Barraud-Lange V, Ravaux B, Howan K, Rodriguez N, Soule P, Ndzoudi A, Boucheix C, Rubinstein E, Wolf JP, Ziyyat A, Perez E, Pincet F, Gourier C 2014 Binding of sperm protein Izumo1 and its egg receptor Juno drives Cd9 accumulation in the intercellular contact area prior to fusion during mammalian fertilization. Development 141:3732-9

    Barraud-Lange V, Naud-Barriant N, Bomsel M, Wolf JP, Ziyyat A 2007 Transfer of oocyte membrane fragments to fertilizing spermatozoa. Faseb J 21:3446-3449

    Barraud-Lange V, Naud-Barriant N, Ducot B, Chambris S, Bomsel M, Wolf JP, Ziyyat A 2009 Cyclic QDE peptide increases fertilization rates and provides healthy pups in mouse. Fertil Steril 91:2110-2115

     

    Funding