Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CFTR expression is regulated during both the cycle of the seminiferous epithelium and the oestrous cycle of rodents

Nature Genetics volume 3, pages 157–164 (1993)Cite this article

Abstract

Severely reduced fertility is a common finding in cystic fibrosis (CF). We used in situ hybridization to examine the cell–specific expression of CFTR in the reproductive organs of rodents. In males CFTR mRNA is found in the round spermatids (spermatogenic stages V–X) and in the principal cells that line the initial segment of the epididymis. In both the testis and the epididymis, CFTR expression is developmentally regulated suggesting that the defect in the genital tract of male CF patients is of developmental origin. CFTR expression in the luminal and glandular epithelium of the uterus is regulated during the oestrous cycle and is maximal at pro–oestrus. Our results provide a biological rationale for the reduced fertility of CF patients, and suggest a possible cause for the comparatively poorer prognosis for women with CF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Rommens, J.M. et al. Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science 245, 1059–1065 (1989).

    Article  CAS  Google Scholar 

  2. Kerem, B.-S. et al. Identification of the cystic fibrosis gene: Genetic analysis. Science 245, 1073–1080 (1989).

    Article  CAS  Google Scholar 

  3. Cheng, S.H. et al. Defective intracellular transport and processing of CFTR is the molecular basis if most cystic fibrosis. Cell 63, 827–834 (1990).

    Article  CAS  Google Scholar 

  4. Kartner, N., Augustinas, O., Jensen, T.J., Naismith, A.L. & Riordan, J.R. Mislocatisation of ΔF508 CFTR in cystic figrosis sweat gland. Nature Genet. 1, 321–327 (1992).

    Article  CAS  Google Scholar 

  5. Anderson, M.P., Rich, D.P., Gregory, R.J., Smith, A.E. & Welsh, M.J. Generation of cAMP-activated chloride currents by expression of CFTR. Science 251, 679–682 (1991).

    Article  CAS  Google Scholar 

  6. Kartner, N. et al. Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance. Cell 64, 681–691 (1991).

    Article  CAS  Google Scholar 

  7. Bear, C.E. et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator. Cell 68, 809–818 (1992).

    Article  CAS  Google Scholar 

  8. Trezise, A.E.O. & Buchwald, M. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature 353, 434–437 (1991).

    Article  CAS  Google Scholar 

  9. Brugman, S.M. & Taussig, L.M. The reproductive system. In Cystic Fibrosis. (ed. Taussig, L.M.) 323–337 (Thieme-Stratton, New York, 1984).

    Google Scholar 

  10. Clermont, Y. Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Phys. Rev. 52, 198–236 (1972).

    CAS  Google Scholar 

  11. Leblond, C.P. & Clermont, Y. Definition of the stages of the cycle of the seminiferous epithelium in the rat. Ann. N.Y. Acad. Sci. 55, 548–573 (1952).

    Article  CAS  Google Scholar 

  12. Hess, R.A. Quantitative and qualitative characteristics of the stages and transitions in the cycle of the rat seminiferous epithelium: light microscopic observations of perfusion-fixed and plastic-embedded testes. Biol. Reprod. 43, 525–542 (1990).

    Article  CAS  Google Scholar 

  13. Morales, C.R., Alcivar, A.A., Hecht, N.B. & Griswold, M.D. Specific mRNAs in sertoli and germinal cells of testes from stage synchronised rats. Molec. Endocrin. 3, 725–733 (1989).

    Article  CAS  Google Scholar 

  14. Russell, L.D., Alger, L.E. & Nequin, L.G. Hormonal control of pubertal spermatogenesis. Endocrinology 120, 1615–1632 (1987).

    Article  CAS  Google Scholar 

  15. Robaire, B. & Hermo, L. Efferent ducts, epididymis, and vas deferens: structure, function and their regulation. In Physiology of Reproduction (eds Knobil, E. & Neill, J.) 999–1080 (Raven Press, New York 1988).

    Google Scholar 

  16. Heaton, N.D. & Pryor, J.P. Vasa aplasia and cystic fibrosis. Br. J. Urol. 66, 538–540 (1990).

    Article  CAS  Google Scholar 

  17. Gottlieb, C., Ploen, L., Kvist, U. & Strandvik, B. The fertility potential of male cystic fibrosis patients. Int. J. Andro. 14, 437–440 (1991).

    Article  CAS  Google Scholar 

  18. Stallard, B.J., Collard, M.W. & Griswold, M.D. A transferrinlike (hemiferrin) mRNA is expressed in the germ cells of rat testis. Molec. cell. Biol. 11, 1448–1453 (1991).

    Article  CAS  Google Scholar 

  19. Crawford, I. et al. Immunocytochemical localisation of the cystic fibrosis gene product CFTR. Proc. natn. Acad. Sci. U.S.A. 88, 9262–9266 (1991).

    Article  CAS  Google Scholar 

  20. Cohn, J.A., Melhus, O., Page, L.J., Dittrich, K.L. & Vigna, S.R. CFTR: development of high-affinity antibodies and localisation in sweat gland. Biochem. Biophys. Res. Comm. 181, 36–43 (1991).

    Article  CAS  Google Scholar 

  21. Quinton, P.M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709–2717 (1990).

    Article  CAS  Google Scholar 

  22. Sprando, R.L. & Russell, L.D. Comparative study of cytoplasmic elimination in spermatids of selected mammalian species. Am. J. Anat. 178, 72–80 (1987).

    Article  CAS  Google Scholar 

  23. Phillips, D.M. Insect sperm: their structure and morphogenesis. J. cell Biol. 44, 243–247 (1970).

    Article  CAS  Google Scholar 

  24. Braun, R.E., Behringer, R.R., Peschon, J.J., Brinster, R.L. & Palmiter, R.D. Genetically haploid spermatids are phenotypically diploid. Nature 337, 373–376 (1989).

    Article  CAS  Google Scholar 

  25. Caldwell, K.A. & Handel, M.A. Protamine transcipt sharing among postmeiotic spermatids. Proc. natn. Acad. Sci. U.S.A. 88, 2407–2411 (1991).

    Article  CAS  Google Scholar 

  26. Murti, J.R., Bumbulis, M. & Schimenti, J.C. High-frequency germ line gene conversion in transgenic mice. Molec. cell Biol. 12, 2545–2552 (1992).

    Article  CAS  Google Scholar 

  27. Schimenti, J. et al. A candidate gene family for the mouse t complex responder (Tcr) locus responsible for haploid effects on sperm function. Cell 55, 71–78 (1988).

    Article  CAS  Google Scholar 

  28. Tsui, L.-C. & Buchwald, M. Biochemical and molecular genetics of cystic fibrosis. Adv. hum. Genet., 20, 153–266 (1991).

    Article  CAS  Google Scholar 

  29. Riordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterisation of complementary DNA. Science 245, 1066–1073 (1989).

    Article  CAS  Google Scholar 

  30. Erikson, R.P. Post-meiotic gene expression. Trends Genet. 6, 264–269 (1990).

    Article  Google Scholar 

  31. Wong, P.Y.D., Au, C.L. & Ngai, H.K. Electrolyte and water transport in rat epididymis; its possible role in sperm maturation. Int. J. Androl. Suppl2, 608–628 (1978).

    Article  Google Scholar 

  32. Wong, P.Y.D. & Yeung, C.H. Absorptive and secretory functions of the perfused rat cauda epididymis. J. Physiol. 275, 13–26 (1978).

    Article  CAS  Google Scholar 

  33. Harris, A., Chalkley, G., Goodman, S. & Coleman, L. Expression of the cystic fibrosis gene in human development. Development 113, 305–310 (1991).

    CAS  PubMed  Google Scholar 

  34. Setchell, B.P. & Brooks, D.E. Anatomy, vasculature, innervation, and fluids of the male reproductive tract. In Physiology of Reproduction (eds Knobil, E. & Neill, J.) 753–836 (Raven Press, New York 1988).

    Google Scholar 

  35. Harper, M.J.K. Gamete and zygote transport. In Physiology of Reproduction (eds Knobil, E. & Neill, J.) 103–134 (Raven Press, New York, 1988).

    Google Scholar 

  36. Arceci, R.J., Croop, J.M., Horwitz, S.B. & Housman, D. The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc. natn. Acad. Sci. U.S.A. 85, 4350–4354 (1988).

    Article  CAS  Google Scholar 

  37. Trezise, A.E.O. et al. The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J. 11, 4291–4303 (1992).

    Article  CAS  Google Scholar 

  38. Valverde, M.A. et al. Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355, 830–833 (1992).

    Article  CAS  Google Scholar 

  39. Snouwaert, J.N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083–1088 (1992).

    Article  CAS  Google Scholar 

  40. Clarke, L.L. et al. Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 257, 1125–1128 (1992).

    Article  CAS  Google Scholar 

  41. Colledge, W.H., Ratcliff, R., Foster, D., Williamson, R. & Evans, M.J. Cystic fibrosis mouse with intestinal obstruction. Lancet 340, 680 (1992).

    Article  CAS  Google Scholar 

  42. Dorin, J.R. et al. Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359, 211–215 (1992).

    Article  CAS  Google Scholar 

  43. Corey, M., McLaughlin, F.J., Williams, M. & Levison, H. A comparison of survival, growth and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J. clin. Epidem. 41, 583–591 (1988).

    Article  CAS  Google Scholar 

  44. Chalon, J., Loew, D.A.Y. & Orkin, L.R. Tracheobronchial cytologic changes during the menstrual cycle. JAMA 218, 1928–1931 (1971).

    Article  CAS  Google Scholar 

  45. Badley, J.E., Bishop, G.A., St John, T. & Frelinger, J.A. A simple, rapid method for the purification of Poly A+ RNA. Biotechniques 6, 114–116 (1988).

    CAS  PubMed  Google Scholar 

  46. Feinberg, A.P. & Vogelstein, B. A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

    Article  CAS  Google Scholar 

  47. Trezise, A.E.O., Szpirer, C. & Buchwald, M. Localisation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) in the rat to chromosome 4 and implications for the evolution of mammalian chromosomes. Genomics 14, 869–874 (1992).

    Article  CAS  Google Scholar 

  48. Simmons, D.M., Arriza, J.L. & Swanson, L.W. A complete protocol for in situ hybridization of messenger RNAs in brain and other tissues with radiolabelled single-stranded RNA probes. J. Histotech. 12, 169–181 (1989).

    Article  CAS  Google Scholar 

  49. Oakberg, E.F. A description of spermiogenesis in the mouse and its use in analysis of the cycle of the seminiferous epithelium and germ cell renewal. Am. J. Anat. 99, 391–413 (1956).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Ann E.O. Trezise

    Present address: Imperial Cancer Research Fund Laboratories, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK

Authors and Affiliations

  1. Department of Genetics, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada

    Ann E.O. Trezise & Manual Buchwald

  2. Biochemistry and Biophysics Program, Washington State University, Pullman, Washington, 99164-4660, USA

    Carol C. Linder & Michael D. Griswold

  3. Division of Endocrinology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada

    David Grieger & Hélène Meunier

  4. Vincent T. Lombardi Cancer Research Centre, Georgetown University Medical Centre, Washington DC, 20007, USA

    Erik W. Thompson

  5. Department of Clinical Biochemistry, University of Toronto, Toronto, Ontario, M5G 1X8, Canada

    Hélène Meunier

  6. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5G 1X8, Canada

    Manual Buchwald

Authors
  1. Ann E.O. Trezise
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol C. Linder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Grieger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erik W. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hélène Meunier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael D. Griswold
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manual Buchwald
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trezise, A., Linder, C., Grieger, D. et al. CFTR expression is regulated during both the cycle of the seminiferous epithelium and the oestrous cycle of rodents. Nat Genet 3, 157–164 (1993). https://doi.org/10.1038/ng0293-157

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0293-157

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing