Institut de recherche biomédicale
     
    Vous êtes ici : Accueil / La Recherche / Développement, Reproduction, Cancer / Equipe 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 sperm motility. For this purpose we combine cell biology, molecular biology and mouse genetics. In addition, in collaboration with the department of Reproductive Biology (Cochin hospital), we develop several programs aiming at defining patho-physiological mechanisms associated with human male infertility.

     

    Participants

    Emma CAVAROCCHI, Master 2 Student
    Marjorie WHITFIELD, Post-doctoral fellow.
    Patrick LORES, ITA (IR2 INSERM).
    Laurence STOUVENEL, ITA (IE1 INSERM).
    Emmanuel DULIOUST, MCU-PH. Reproductive Biology (Cochin hospital).
    Jean-Philippe WOLF / Catherine PATRAT, PU-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: 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

    Ion fluxes play an essential role in the control of sperm motility and capacitation, a maturation event that occurs in the female genital tract and is required for fertilization. In particular, calcium, chloride, and bicarbonate influxes induce an increase in intracellular cyclic AMP concentration, leading to the activation of protein kinase A and phosphorylation cascades required for sperm motility and capacitation. We have previously identified SLC26A8 (TAT1, testis Anion Transporter 1) as an anion transporter exclusively expressed in the sperm and required for sperm motility in the mouse by activating the PKA pathway (Touré et al. Hum Mol Genet 2007). Interestingly we showed that SLC26A8 physically interacts with the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) and strongly stimulates its activity, indicating that TAT1 and CFTR form a molecular complex involved in the regulation of anion fluxes during sperm capacitation (Rode et al. Hum Mol Genet 2012). We subsequently demonstrated the physiological relevance of this cooperation by the identification of several mutations in the TAT1 gene impacting on the stability and the activity of the CFTR/TAT1 complex and associated with human asthenozoospermia (Dirami et al. Am J Hum Genet 2013). Our work emphasizes the general importance of SCL26/CFTR cooperation in the processes of ion regulation within various tissues and cell types (El Khouri & Toure, Intern. J. Bioch. Cell Biol. 2014- Review ; Touré. Monogr Hum Genet 2017-Review).

    We are aslo interested in the mechanisms regulating flagellum assembly during spermiogenesis and have studied the annulus, a Septin-ring structure located at the junction of the midpiece and the principal piece of mammalian flagellum. The annulus is formed in the round spermatids at 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 showed that the sperm specific anion channel SLC26A8 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 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).

    Besides, by analysing 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 or syndromic (Primary Ciliary Dyskinesia) male infertility (El Khouri et al. Am J Hum Genet 2016; Lorès et al. Hum Mol Genet 2018; Coutton et al. Nature Comm 2018, Dong et al. Am JHum Genet 2018)

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

     

    Selected publications

    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.

    Dong FN, Amiri-Yekta A, Martinez G, Saut A, Tek J, Stouvenel L, Lorès P, Karaouzène T, Thierry-Mieg N, Satre V, Brouillet S, Daneshipour A, Hosseini SH, Bonhivers M, Gourabi H, Dulioust E, Arnoult C, Touré A, Ray PF, Zhao H, Coutton C. Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse. Am J Hum Genet. 2018 102(4):636-648

    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 27(7):1196-1211

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

    Touré A. Genetics and Pathophysiology of the Cystic Fibrosis Transmembrane Conductance Regulator in Male Reproduction: New Evidence of a Direct Effect on the Male Germline. (Book chapter). Genetics of Human Infertility. Monogr Hum Genet. Basel, Karger, 2017, vol 21, pp 74-85.

    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 99(2):489-500.

    Mitchell M, Metzler-Guillemain C, Touré A, Coutton C, Arnoult C and Ray PF. Single gene defects leading to sperm quantitative anomalies. (Review). Clin Genet. 2017 91(2):208-216.

    Ray PF, Touré A, Metzler-Guillemain C, Mitchell M, Arnoult C and Coutton C. Genetic abnormalities leading to qualitative defects of sperm morphology or function. (Review). Clin Genet. 2017 91(2):217-232

    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

    El Khouri, E. and Touré A. Functional Interaction of the Cystic Fibrosis Transmembrane conductance Regulator with members of the SLC26 family of anion transporters (SLC26A8 and SLC26A9): physiological and pathophysiological relevance. (Review). Intern. J. Bioch. Cell Biol. 2014 Jul;52:58-67

    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

    Rode B, Dirami T, Bakouh N, Rizk-Rabin M, Norez C, Lhuillier P, Lorès P, Jollivet M, Melin P, Zvetkova I, Bienvenu T, Becq F, Planelles G, Edelman A, Gacon G and Touré A. The Testis Anion Transporter TAT1 (SLC26A8) stimulates CFTR activity during sperm capacitation. Hum Mol Genet. 2012, 21(6):1287-98.

     

    Funding