Biomedical research institute
     
    You are here: Home / Departments / Development, Reproduction and Cancer / Team D. Vaiman / Spermatogenesis & infertility: Sperm structure & motility

    Spermatogenesis & infertility: Sperm structure & motility

     

     

    Project leader

    +33 144412310

     

    Research Topics

    Our group is interested in understanding the molecular mechanisms, which control sperm flagellum assembly and structure, together with sperm motility and fertilization potential. For this purpose, we combine cell biology, molecular biology, biochemistry and mouse genetics. In addition, in collaboration with the department of Reproductive Biology (Cochin hospital), we aim at defining some of the genetic causes and patho-physiological mechanisms associated with human male infertility.

     

    Participants

    Emma CAVAROCCHI, PhD Student.

    Marjorie WHITFIELD, Post-doctoral fellow.Patrick LORES, Engineer (IR2 INSERM).

    Laurence STOUVENEL, Engineer (IE1 INSERM).

    Emmanuel DULIOUST, M.D, PhD (MCU-PH). Reproductive Biology - Cochin hospital.

    Aminata TOURE, Principal Investigator (DR2 CNRS).

     

     

    Alumni

     

    Post-doctoral Fellows: Charles Coutton (2017), Elma El Khouri (2013-2016).

    PhD Students: Thassadite Dirami (2009-2012), Baptiste Rode (2007-2011), Pierre Lhuillier (2004-2008).

    Master Students: Emma Cavarocchi (M2-2018), Jean-Fabrice Nsota Mbango (M2-2016), Julie Tek (M2-2016), Marhaba Chaudhry (M2-2015), Precilia Homand (M2-2015), Zeinab Sakheli (M2-2014), Maelle Givelet (M2-2013), Rabah Tamoumi (M1-2012), Nathalie Da Silva (M2-2011), Lucie Puron (M1-2011),

    Audrey Chansard (M1-2010), Thassadite Dirami (M2-2008 and M1-2007), Baptiste Rode (M2-2006), Sébastien Pichon (M1-2006).

     

    Recent achievements

    Our group is interested in defining the molecular and cellular mechanisms regulating the assembly and the structure of the sperm flagellum in mammals. We have investigated the role of the annulus, a Septin-ring structure located at the junction of the midpiece and the principal piece of mammalian flagellum, in this process. The annulus is formed in the round spermatids at the very early stages of flagellum assembly, concomitant with nucleus condensation and the development of the acrosome. It has been suggested that the annulus acts as a morphological organizer, guiding flagellum assembly during spermiogenesis, and as a diffusion barrier, confining proteins to distinct compartments of the flagellum in mature sperm. We have shown that the sperm specific anion channel SLC26A8 (TAT1) specifically locates to this structure and might anchor the Septin polymers to the plasma membrane, thus being required for proper flagellum structure (Toure et al. Biol Chem 2011-Review). We also have reported the association of annulus defects in asthenozoospermia (Lhuillier et al. Hum Reprod 2009) and provided an accurate frequency of these defects in human male infertility by analysis of large cohorts of asthenozoospermic individuals (Dirami et al. Basic Clin Andrology 2015). In parallel, by analysing several cohorts of infertile patients, we aimed at identifying some of the pathophysiological mechanisms associated with sperm structural and functional defects in humans. In this regard, we recently identified several genetic causes of human asthenozoospermia, which are responsible for isolated male infertility or syndromic male infertility (Primary Ciliary Dyskinesia) (see review Nsota Mbango et al. 2019). 

    Importantly, while spermatozoa produced in the testis are structurally differentiated, they remain immotile and are unable to fertilize the oocyte unless they undergo a series of maturation events during their transit in the male and female genital tracts. This post-testicular functional maturation is known to rely on the micro-environment of both male and female genital tracts, and is tightly controlled by the ion content and the pH of their luminal milieu. Hence ion fluxes play an essential role in the control of sperm motility and capacitation, which occurs in the female genital tract. In particular, calcium, chloride, and bicarbonate influxes induce an increase in intracellular cyclic AMP concentration, leading to the activation of PKA and phosphorylation cascades, which are essential for the fertilization potential.  Our group was pioneer in investigating the functions of SLC26 transmembrane anion exchangers in sperm cells and showed that the sperm specific SLC26A8 protein is required for sperm motility and capacitation, both in mice and in humans, by activating the cAMP-PKA pathway in cooperation with the CFTR channel (Touré et al. Hum Mol Genet 2007; Rode et al. Hum Mol Genet 2012; Dirami et al. Am J Hum Genet 2013). Recently we also demonstrated that SLC26A3, mainly expressed in the gastro-intestinal tract, is also required within the sperm cells and the epididymal cells to confer proper sperm maturation and fertilization potential (EL Khouri et al. Mol Reprod Devel 2018). Overall, our work indicates that SLC26A3 and SLC26A8 constitute important regulators of anion fluxes in the processes of sperm maturation and activation (Toure. Review - Frontiers in Cell Dev 2019). It also emphasizes the general importance of SCL26/CFTR cooperation in the processes of ion regulation within various epithelia and cell types (El Khouri and Touré. Review - Intern. J. Bioch. Cell Biol.2014; Touré. Review - Monogr Hum Genet 2017).  

    Key words: spermatozoa, flagellum, cilia, annulus, SLC26, CFTR, asthenozoospermia, male infertility.

     

     

    Selected publications

    Lorès P, Dacheux D, Kherraf Z-E, Nsota Mbango J-F, Coutton C, Stouvenel S, Ialy-Radio C,  Amiri-Yekta A, Whitfield  M,  Schmitt A, Cazin C, Givelet M,  Ferreux L,  Fourati Ben Mustapha S, Halouani L, Marrakchi O, Daneshipour A, El Khouri E, Do Cruzeiro M, Favier M, Guillonneau F, Chaudhry M, Sakheli Z, Wolf J-P,  Patrat C,  Gacon G, Savinov S. N, Hosseini S, Robinson D.R, Zouari R, Ziyyat A, Arnoult C, Dulioust E, Bonhivers M, Ray P.F and Touré A. Mutations in TTC29, encoding an evolutionary conserved axonemal protein, result in asthenozoospermia and male infertility. Am J Hum Genet. 2019 Dec 5; 105: 1-20

    Touré A. Importance of SLC26 transmembrane anion exchangers in sperm post-testicular maturation and fertilization potential (Review). Front Cell Dev Biol. 2019 Oct 18;7:230.

    Whitfield M, Thomas L, Bequignon E, Schmitt A, Stouvenel L, Montantin G, Tissier S, Duquesnoy P, Copin B, Chantot S, Dastot F, Faucon C, Barbotin AL, Loyens A, Siffroi JP, Papon JF, Escudier E, Amselem S, Mitchell V*, Touré A** and Legendre M*. ¬Mutations in DNAH17, encoding a sperm-specific axonemal outer dynein arm heavy chain, cause isolated male infertility due to asthenozoospermia. Am J Hum Genet. 2019 Jul 3;105(1):198-212.

    Nsota Mbango J-F, Coutton C, Arnoult C, Ray P, and Toure A, Genetic causes of male infertility: Snapshot on Morphological Abnormalities of the Sperm Flagellum (Review). Basic Clin Androl. 2019; Mar 4;29:2.

    El Khouri E, Whitfield M, Stouvenel L, Kini A, Riederer B, Lores P, Roemermann D, di Stefano G, Drevet JR, Saez F, Seidler U, Touré A. Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse. Mol Reprod Dev. 2018 Aug;85(8-9):682-695

    Coutton C, Vargas AS, Amiri-Yekta A, Kherraf ZE, Ben Mustapha SF, Le Tanno P, Wambergue-Legrand C, Karaouzène T, Martinez G, Crouzy S, Daneshipour A, Hosseini SH, Mitchell V, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, DeleuzeJF, Boland A, Hennebicq S, Satre V, Jouk PS, Thierry-Mieg N, Conne B, Dacheux D, Landrein N, Schmitt A, Stouvenel L, Lorès P, El Khouri E, Bottari SP, Fauré J,Wolf JP, Pernet-Gallay K, Escoffier J, Gourabi H, Robinson DR, Nef S, Dulioust E, Zouari R, Bonhivers M, Touré A*, Arnoult C*, Ray PF*. Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human. Nat Commun. 2018 Feb 15;9(1):686.

    Lorès P*, Charles Coutton C*, Khouri E*, Stouvenel L, Maëlle Givelet M, Thomas L, Rode B, Schmitt A, Louis B, Sakheli Z, Chaudhry M, Fernandez-Gonzales A, Mitsialis A, Dacheux D, Wolf JP, Papon JF, Gacon G, Escudier E, Arnoult A, Bonhivers B, Savinov SN, Amselem S, Ray PF*, Dulioust E* and Touré A*. Homozygous missense mutation L673P in Adenylate Kinase 7 (AK7) leads to primary male infertility and Multiple Morphological Anomalies of the Flagella but not to Primary Ciliary Dyskinesia. Hum Mol Genet. 2018 Jan 22.

    El Khouri E, Thomas L, Jeanson L, Bequignon E, Vallette B, Duquesnoy P, Montantin G, Copin B, Dastot-Le Moal F, Blanchon S, Papon JF, Lorès P, Yuan L, Collot N, Tissier S, Faucon C, Gacon G, Patrat C, Wolf JP, Dulioust E, Crestani B, Escudier E, Coste A, Legendre M, Touré A*, Amselem S*. Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility. Am J Hum Genet. 2016 Aug 4;99(2):489-500.  

    Dirami T, Rode B, Wolf JP, Gacon G, Dulioust E and Touré A. Assessment of the frequency of sperm annulus defects in a large cohort of patients presenting asthenozoospermia. Basic Clin.  Androl. 2015 Nov 15;25:10

    Lorès P, Vernet N, Kurosaki T, Van de Putte T, Huylebroeck D, Hikida M, Gacon G and Touré, A. Deletion of MgcRacGAP in the male germ cells impairs spermatogenesis and causes male sterility in the mouse. Dev Biol. 2014 Feb 15;386(2):419-27

    Dirami, T., Rode, B., Jollivet, M., Da Silva, N., Escalier, D., Gaitsch, N., Norez, C., Tuffery, P., Wolf, JP., Becq, F., Ray, PF., Dulioust, E., Gacon, G., Bienvenu, T. and Touré, A. Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia. Am J. Hum. Genet. 2013 May 2;92(5):760-6

     

    Funding