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Journal of Endocrinological Investigation

, Volume 23, Issue 9, pp 609–615 | Cite as

Role of c-kit in mammalian spermatogenesis

  • P. Rossi
  • C. Sette
  • S. Dolci
  • R. Geremia
Article

Abstract

The tyrosine-kinase receptor c-kit and its ligand, stem cell factor (SCF), are essential for the maintenance of primordial germ cells (PGCs) in both sexes. However, c-kit and a postmeiotic- specific alternative c-kit gene product play important roles also during post-natal stages of spermatogenesis. In the adult testis, the c-kit receptor is re-expressed in differentiating spermatogonia, but not in spermatogonial stem cells, whereas SCF is expressed by Sertoli cells under FSH stimulation. SCF stimulates DNA synthesis in type A spermatogonia cultured in vitro, and injection of anti-c-kit antibodies blocks their proliferation in vivo. A point mutation in the c-kit gene, which impairs SCF-mediated activation of phosphatydilinositol 3-kinase, does not cause any significant reduction in PGCs number during embryonic development, nor in spermatogonial stem cell populations. However males are completely sterile due to a block in the initial stages of spermatogenesis, associated to abolishment of DNA-synthesis in differentiating A1-A4 spermatogonia. With the onset of meiosis c-kit expression ceases, but a truncated c-kit product, tr-kit, is specifically expressed in post-meiotic stages of spermatogenesis, and is accumulated in mature spermatozoa. Microinjection of tr-kit into mouse eggs causes their parthenogenetic activation, suggesting that it might play a role in the final function of the gametes, fertilization.

Key-words

C-kit stem cell factor spermatogenesis fertilization 

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References

  1. 1.
    Besmer P., Murphy J.E., George P.C., Qiu F.H., Bergold P.J., Lederman L., Snyder H.W. Jr., Brodeur D., Zuckerman, E.E., Hardy W.D. A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 1986, 320: 415–421.PubMedCrossRefGoogle Scholar
  2. 2.
    Yarden Y., Kuang W.J., Yang-Feng T., Coussens L., Munemitsu S., Dull T.J., Chen E., Schlessinger J., Francke U., Ullrich A. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987, 6: 3341–3351.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Qiu F., Ray P., Barker P.E., Jhanwar S., Ruddle F.H., Besmer P. Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family-oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. EMBO J. 1988, 7: 1003–1011.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Chabot B., Stephenson D.A., Chapman V.M., Besme P., Bernstein A. The protooncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988, 335: 88–89.PubMedCrossRefGoogle Scholar
  5. 5.
    Geissler E.N., Ryan M.A., Housman D.E. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 1988, 55: 185–192.PubMedCrossRefGoogle Scholar
  6. 6.
    Russell E.S. Hereditary anemias of the mouse: a review for geneticists. Adv. Genet. 1979, 20: 357–459.PubMedCrossRefGoogle Scholar
  7. 7.
    Witte O.N. Steel locus defines new multipotent growth factor. Cell 1990, 63: 5–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Besmer P. The kit ligand encoded at the murine steel locus: a pleiotropic growth and differentiation factor. Curr. Opin. Cell. Biol. 1991, 3: 939–946.PubMedCrossRefGoogle Scholar
  9. 9.
    Williams D.E., de Vries P., Namen A.E., Widmer M.B., Lyman S.D. The Steel factor. Dev. Biol. 1992, 151: 368–376.PubMedCrossRefGoogle Scholar
  10. 10.
    Flanagan J.F., Chan D.C., Leder P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 1991, 64:1025–1035.PubMedCrossRefGoogle Scholar
  11. 11.
    Matsui Y., Zsebo K.M., Hogan B.L. Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature 1990, 347: 667–669.PubMedCrossRefGoogle Scholar
  12. 12.
    Dolci S., Williams D.E., Ernst M.K., Resnick J.L., Brannan C.I., Lock L.F., Lyman S.D., Boswell H.S., Donovan P.J. Requirement for mast cell growth factor for primordial germ cell survival in culture. Nature 1991, 352: 809–811.PubMedCrossRefGoogle Scholar
  13. 13.
    Godin I., Deed R., Cooke J., Zsebo K., Dexter M., Wylie C.C. Effects of the steel gene product on mouse primordial germ cells in culture. Nature 1991, 352: 807–809.PubMedCrossRefGoogle Scholar
  14. 14.
    Matsui Y., Toksoz D., Nishikawa S., Nishikawa S., Williams D., Zsebo K., Hogan B.L. Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture. Nature 1991, 353: 750–752.PubMedCrossRefGoogle Scholar
  15. 15.
    Pesce M., Farrace M.G., Piacentini M., Dolci S., De Felici M. Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 1993, 118:1089–1094.PubMedGoogle Scholar
  16. 16.
    Manova K., Bachvarova R.F. Expression of c-kit encoded at the W locus of mice in developing embryonic germ cells and presumptive melanoblasts. Dev. Biol. 1991, 146: 312–324.PubMedCrossRefGoogle Scholar
  17. 17.
    Manova K., Nocka K., Besmer P., Bachvarova R.F. Gonadal expression of c-kit encoded at the W locus of the mouse. Development 1990, 110: 1057–1069.PubMedGoogle Scholar
  18. 18.
    Sorrentino V., Giorgi M., Geremia R., Besmer P., Rossi P. Expression of the c-kit protooncogene in the murine male germ cells. Oncogene 1991, 6: 149–151.PubMedGoogle Scholar
  19. 19.
    Motro B., van der Kooy D., Rossant J., Reith A., Bernstein A. Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci. Development 1991, 113: 1207–1221.PubMedGoogle Scholar
  20. 20.
    Yoshinaga K., Nishikawa S., Ogawa M., Hayashi S., Kunisada T., Fujimoto T., Nishikawa S.-I. Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function. Development 1991, 113: 689–699.PubMedGoogle Scholar
  21. 21.
    Dym M., Jia M.C., Dirami G., Price J.M., Rabin S.J., Mocchetti I., Ravindranath N. Expression of c-kit receptor and its autophosphorylation in immature rat type A spermatogonia. Biol. Reprod. 1995, 52: 8–19.PubMedCrossRefGoogle Scholar
  22. 22.
    Albanesi C., Geremia R., Giorgio M., Dolci S., Sette C., Rossi P. A cell-and developmental stage-specific promoter drives the expression of a truncated c-kit protein during mouse spermatid elongation. Development 1996, 122: 1291–1302.PubMedGoogle Scholar
  23. 23.
    Natali P.G., Nicotra M.R., Sures I., Santoro E., Bigotti A., Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992, 52: 6139–6143.PubMedGoogle Scholar
  24. 24.
    Sandlow J.I., Feng H.L., Cohen M.B., Sandra A. Expression of c-kit and its ligand, stem cell factor, in normal and subfertile human testicular tissue. J. Androl. 1996, 17: 403–408.PubMedGoogle Scholar
  25. 25.
    von Schonfeldt V., Krishnamurthy H., Foppiani L., Schlatt S. Magnetic cell sorting is a fast and effective method of enriching viable spermatogonia from Djungarian hamster, mouse, and marmoset monkey testes. Biol. Reprod. 1999, 61: 582–589.CrossRefGoogle Scholar
  26. 26.
    Schrans-Stassen B.H., van de Kant H.J., de Rooij D.G., van Pelt A.M. Differential expression of c-kit in mouse undifferentiated and differentiating type A spermatogonia. Endocrinology 1999, 140: 5894–5900.PubMedCrossRefGoogle Scholar
  27. 27.
    Rossi P., Marziali G., Albanesi C., Charlesworth A., Geremia R., Sorrentino V. A novel c-kit transcript, potentially encoding a truncated receptor, originates within a kit gene intron in mouse spermatids. Dev. Biol. 1992, 152: 203–207.PubMedCrossRefGoogle Scholar
  28. 28.
    Vincent S., Segretain D., Nishikawa S., Nishikawa S.I., Sage J., Cuzin F., Rassoulzadegan M. Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit-KL interaction critical for meiosis. Development 1998, 125: 4585–4593.PubMedGoogle Scholar
  29. 29.
    Rossi P., Albanesi C., Grimaldi P., Geremia R. Expression of the mRNA for the ligand of c-kit in mouse Sertoli cells. Biochem. Biophys. Res. Commun. 1991, 176: 910–914.PubMedCrossRefGoogle Scholar
  30. 30.
    Rossi P., Dolci S., Albanesi C., Grimaldi P., Ricca R., Geremia R. FSH induction of Steel Factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Dev. Biol. 1993, 155: 68–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Manova K., Huang E.J., Angeles M., De Leon V., Sanchez S., Pronovost S.M., Besmer P., Bachvarova R.F. The expression pattern of the c-kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia. Dev. Biol. 1993, 157: 85–99.PubMedCrossRefGoogle Scholar
  32. 32.
    Tajima Y., Onoue H., Kitamura Y., Nishimune Y. Biologically active kit ligand growth factor is produced by mouse Sertoli cells and is defective in SId mutant mice. Development 1991, 113: 1031–1035.PubMedGoogle Scholar
  33. 33.
    Marziali G., Lazzaro D., Sorrentino V. Binding of germ cells to mutant Sld Sertoli cells is defective and is rescued by expression of the transmembrane form of the c-kit ligand. Dev. Biol. 1993, 157: 182–190.PubMedCrossRefGoogle Scholar
  34. 34.
    Munsie M., Schlatt S., deKretser D.M., Loveland K.L. Expression of stem cell factor in the postnatal rat testis. Mol. Reprod. Dev. 1997, 47: 19–25.PubMedCrossRefGoogle Scholar
  35. 35.
    Yan W., Linderborg J., Suominen J., Toppari J. Stage-specific regulation of stem cell factor gene expression in the rat seminiferous epithelium. Endocrinology 1999, 140: 1499–1504.PubMedGoogle Scholar
  36. 36.
    Parvinen M. Regulation of the seminiferous epithelium. Endocr. Rev. 1982, 3: 404–417.PubMedCrossRefGoogle Scholar
  37. 37.
    Mauduit C., Chatelain G., Magre S., Brun G., Benahmed M., Michel D. Regulation by pH of the alternative splicing of the stem cell factor pre-mRNA in the testis. J. Biol. Chem. 1999, 274: 770–775.PubMedCrossRefGoogle Scholar
  38. 38.
    Koshimizu U., Sawada K., Tajima Y., Watanabe D., Nishimune Y. White-spotting mutations affect the regenerative differentiation of testicular germ cells: demonstration by experimental cryptorchidism and its surgical reversal. Biol. Reprod. 1991, 45: 642–648.PubMedCrossRefGoogle Scholar
  39. 39.
    Brannan C.I., Bedell M.A., Resnick J.L., Eppig J.J., Handel M.A., Williams D.E., Lyman S.D., Donovan P.J., Jenkins N.A., Copeland N.G. Developmental abnormalities in Steel17H mice result from a splicing defect in the steel factor cytoplasmic tail. Genes Dev. 1992, 6: 1832–1842.PubMedCrossRefGoogle Scholar
  40. 40.
    Hakovirta H, Yan W., Kaleva M., Zhang F., Vanttinen K., Morris P.L., Sode M., Parvinen. M., Toppari J. Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium. Endocrinology 1999, 140: 1492–1498.PubMedGoogle Scholar
  41. 41.
    Tajima Y., Sawada K., Morimoto T., Nishimune Y. Switching of mouse spermatogonial proliferation from the c-kit receptor-independent type to the receptor-dependent type during differentiation. J. Reprod. Fertil. 1994, 102: 117–122PubMedCrossRefGoogle Scholar
  42. 42.
    Packer A.I., Besmer P., Bachvarova R.F. Kit ligand mediates survival of type A spermatogonia and dividing spermatocytes in postnatal mouse testes. Mol. Reprod. Dev. 1995, 42: 303–310.PubMedCrossRefGoogle Scholar
  43. 43.
    Yan W., Suominen J., Toppari J. Stem cell factor protects germ cells from apoptosis in vitro. J. Cell Sci. 2000, 113: 161–168.PubMedGoogle Scholar
  44. 44.
    Allard E.K., Blanchard K.T., Boekelheide K. Exogenous stem cell factor (SCF) compensates for altered endogenous SCF expression in 2,5-hexanedione-induced testicular atrophy in rats. Biol. Reprod. 1996, 55: 185–193.PubMedCrossRefGoogle Scholar
  45. 45.
    Dirami G., Ravindranath N., Pursel V., Dym M. Effects of stem cell factor and granulocyte macrophage-colony stimulating factor on survival of porcine type A spermatogonia cultured in KSOM. Biol. Reprod. 1999, 61: 225–230.PubMedCrossRefGoogle Scholar
  46. 46.
    Dym M. Spermatogonial stem cells of the testis. Proc. Natl. Acad. Sci USA 1994, 91: 11287–11289.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Tajima Y., Sakamaki K., Watanabe D., Koshimizu U., Matsuzawa T., Nishimune Y. Steel-Dickie (Sld) mutation affects both maintenance and differentiation of testicular germ cells in mice. J. Reprod. Fertil. 1991, 91: 441–449.PubMedCrossRefGoogle Scholar
  48. 48.
    Timokhina I., Kissel H., Stella G., Besmer P. Kit signaling through PI 3-kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation. EMBO J. 1998, 17: 6250–6262.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    De Sepulveda P., Okkenhaug K., Rose J.L., Hawley R.G., Dubreuil P., Rottapel R. Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. EMBO J. 1999, 18: 904–915.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Blume-Jensen P., Jiang G., Hyman R., Lee K.F., O’Gorman S., Hunter T. Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3’-kinase is essential for male fertility. Nat. Genet. 2000, 24: 157–162.PubMedCrossRefGoogle Scholar
  51. 51.
    Kissel H., Timokhina I., Hardy M.P., Rothschild G., Tajima Y., Soares V., Angeles M., Whitlow S.R., Manova K., Besmer P. Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses. EMBO J. 2000, 19: 1312–1326.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Serve H., Hsu Y.C., Besmer P. Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells. J. Biol. Chem. 1994, 269: 6026–6030.PubMedGoogle Scholar
  53. 53.
    Blume-Jensen P., Janknecht R., Hunter T. The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr. Biol. 1998, 8: 779–782.PubMedCrossRefGoogle Scholar
  54. 54.
    Ohta H., Yomogida K., Dohmae K., Nishimune Y. Regulation of proliferation and differentiation in permatogonial stem cells: the role of c-kit and its ligand SCF. Development 2000, 127: 2125–2131.PubMedGoogle Scholar
  55. 55.
    Herrmann B.G., Koschorz B., Wertz K., McLaughlin K.J., Kispert A. A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. Nature 1999, 402: 141–146.PubMedCrossRefGoogle Scholar
  56. 56.
    Sette C., Bevilacqua A., Bianchini A., Mangia F., Geremia R., Rossi P. Parthenogenetic activation of mouse eggs by microinjection of a truncated c-kit tyrosine kinase present in spermatozoa. Development 1997, 124: 2267–2274.PubMedGoogle Scholar
  57. 57.
    Sette C., Bevilacqua A., Geremia R., Rossi P. Involvement of phospholipase C g1 in mouse egg activation induced by a truncated form of the c-kit tyrosine kinase present in spermatozoa. J. Cell Biol. 1998, 142: 1063–1074.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2000

Authors and Affiliations

  1. 1.Dipartimento di Sanità Pubblica e Biologia Cellulare, Sezione di AnatomiaUniversità “Tor Vergata”RomaItaly

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