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:

Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting

Abstract

Kallmann syndrome is a genetic disorder characterized by a defect in olfactory system development, which appears to be due to an abnormality in the migration of olfactory axons and gonadotropin releasing hormone (Gn–RH) producing neurons. The X–linked Kallmann syndrome gene shares significant similarities with molecules involved in neural development. We have now isolated the evolutionarily conserved chicken homologue of the Kallmann gene. In the developing and adult chicken, high levels of expression were found in the mitral cells of the olfactory bulb (the target of olfactory axons) and in the Purkinje cells of the cerebellar cortex, both areas affected in patients with Kallmann syndrome. We propose a model in which the Kallmann syndrome gene product is a signal molecule required for neuronal targeting throughout life.

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

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

Similar content being viewed by others

References

  1. Shepherd, G.M. & Greer, C.A. Olfactory bulb. In The Synaptic Organization of The Brain (ed. Shepherd G. M.) 133–169 (Oxford University Press, Oxford, 1990).

    Google Scholar 

  2. Monti Graziadei, G.A. & Graziadei, P.P.C. Studies on neuronal plasticity and regeneration in the olfactory system: morphologic and functional characteristics of the olfactory sensory neuron. In Neural growth and differentiation (eds Meisami E. & Brazier M. A. B.) 373–396 (Raven Press, New York, 1979).

    Google Scholar 

  3. Brunjes, P.C. & Frazier, L.L. Maturation and plasticity in the olfactory system of vertebrates. Brain Res. Rev. 11, 1–45 (1986).

    Article  Google Scholar 

  4. Shepherd, G.M. Modules for molecules. Nature 358, 457–458 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Kallmann, F., Schoenfeld, W.A. & Barrera, S.E. The genetic aspects of primary eunuchoidism. Am. J. Ment. Defic. 48, 203–236 (1944).

    Google Scholar 

  6. DeMorsier, G. Etudes sur les dysraphies cranio-encephaliques. Schweiz. Arch. Neurol. Neurochir. Psychiat. 74, 309–361 (1954).

    CAS  Google Scholar 

  7. Klingmüller, D., Dewes, W., Krahe, T., Brecht, G. & Schweikert, H.-U. Magnetic resonance imaging of the brain in patients with anosmia and hypothalamic hypogonadism (Kallmann's syndrome). J. clin. endocrinol. Metab. 65, 581–584 (1987).

    Article  PubMed  Google Scholar 

  8. Naftolin, F., Harris, G.W. & Bobrow, M. Effect of purified luteinizing hormone releasing factor on normal and hypogonadotropic anosmic men. Nature 232, 496–497 (1971).

    Article  CAS  PubMed  Google Scholar 

  9. Sunohara, N., Sakuragawa, N., Satoyoshi, E., Tanae, A. & Shapiro, L.J. A new syndrome of anosmia, hypogonadism and various neurological manifestations with deficiency of steroid sulfatase and arylsulfatase C. Ann. Neurol. 19, 174–181 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Schwankhaus, J.D., Currie, J., Jaffe, M.J., Rose, S.R. & Sherins, J. Neurologic findings in men with isolated hypogonadotropic hypogonadism. Neurology 39, 223–226 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Wegenke, J.D. et al. Familial Kallmann syndrome with unilateral renal aplasia. Clinic. Genet. 7, 368–381 (1975).

    Article  CAS  Google Scholar 

  12. White, B.J., Rogol, A.D., Brown, S.K., Lieblich, J.M. & Rosen, S.W. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am. J. med. Genet. 15, 417–435 (1983).

    Article  CAS  PubMed  Google Scholar 

  13. Hardelin, J.P. et al. X-chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc. natn. Acad. Sci. U.S.A. 89, 8190–8194 (1992).

    Article  CAS  Google Scholar 

  14. Schwanzel-Fukuda, M. & Pfaff, D.W. Origin of luteinizing hormone-releasing hormone neurons. Nature 338, 161–164 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Wray, S., Grant, P. & Gainer, H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc. natn. Acad. Sci. U.S.A. 86, 8132–8136 (1989).

    Article  CAS  Google Scholar 

  16. Schwanzel-Fukuda, M. & Pfaff, D.W. The migration of luteinizing hormone-releasing hormone (LH-RH) neurons from the medial olfactory placode into the medial basal forebrain. Experientia 46, 956–961 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Schwanzel-Fukuda, M., Bick, D. & Pfaff, D.W. Luteinizing hormone-releasing hormone (LH-RH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Molec. Brain Res. 6, 311–326 (1989).

    Article  CAS  PubMed  Google Scholar 

  18. Franco, B. et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353, 529–536 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Legouis, R. et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67, 423–435 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Bick, D. et al. Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome. New Engl. J. Med. 326, 1752–1755 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Drenth, J., Low, B.M., Richardson, J.S. & Wright, C.S. The toxin-agglutinin fold. J. biol. Chem. 255, 2652–2655 (1980).

    CAS  PubMed  Google Scholar 

  22. Lander, A.D. Understanding the molecules of neural cell contacts: emerging patterns of structure and function. Trends Neurosci. 12, 189–195 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Fisher, E.H., Charbonneau, H. & Tonks, N.K. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science 253, 401–406 (1991).

    Article  Google Scholar 

  24. Black, J.E., Isaacs, K.R., Anderson, B.J., Alcantara, A.A. & Greenough, W.T. Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc. natn. Acad. Sci. U.S.A. 87, 5568–5572 (1990).

    Article  CAS  Google Scholar 

  25. Hamburger, V. & Hamilton, H.L. A series of normal stages in the development of the chick embryo. J. Morph. 88, 49–92 (1951).

    Article  CAS  PubMed  Google Scholar 

  26. Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucl. Acids Res. 12, 857–872 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ferguson, M.A.J. & Williams, A.F. Cell-surface anchoring of proteins via glycosyl-phosphatidylinositol structures. Ann. Rev. Biochem. 57, 285–320 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Kyte, J.P. & Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. molec. Biol. 157, 105–132 (1982).

    Article  CAS  PubMed  Google Scholar 

  29. Hinds, J.W. Early neuron differentiation in the mouse olfactory bulb. I. Light microscopy. J. comp. Neurol. 146, 233–252 (1972).

    Article  CAS  PubMed  Google Scholar 

  30. Youngren, O.M. & Phillips, R.E. A stereotaxic atlas of the brain of the three-day-old domestic chick. J. Comp. Neurol. 181, 567–600 (1978).

    Article  CAS  PubMed  Google Scholar 

  31. Bessette, B.B. & Hodos, W. Intensities, color, and pattern discrimination deficits after lesion of the core and belt regions of the ectostriatum. Visual Neurosci. 2, 27–34 (1989).

    Article  CAS  Google Scholar 

  32. Reichardt, L.F. & Tomaselli, K.J. Extracellular matrix molecules and their receptors: functions in neural development. Ann. Rev. Neurosci. 14, 531–570 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Grompe, M., Pieretti, M., Caskey, C.T. & Ballabio, A. The sulfatase gene family: cross-species PCR cloning using the MOPAC technique. Genomics 12, 755–760 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Murakami, S., Seki, T., Wakabayashi, K. & Arai, Y. The ontogeny of luteinizing hormone-releasing hormone (LHRH) producing neurons in the chick embryo: possible evidence for migrating LHRH neurons from the olfactory epithelium expressing a highly polysialylated neural cell adhesion molecule. Neurosci. Res. 12, 421–431 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Ballabio, A. & Camerino, G. The gene for X-linked Kallmann syndrome: a human monoclonal migration defect. Curr. Op. Genet. Dev. 2, 417–421 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Calof, A.L. Sex, nose and genotype. Curr. Biol. 2, 103–105 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Caviness, V.S. Kallmann's syndrome: beyond “migration”. New Eng. J. Med. 326, 1775–1776 (1992).

    Article  PubMed  Google Scholar 

  38. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  39. Gibbs, R., Nguyen, P.N., McBride, L.J., Koepf, S.M. & Caskey, C.T. Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc. natn. Acad. Sci. U.S.A. 86, 1919–1923 (1989).

    Article  CAS  Google Scholar 

  40. Genetics Computer Group Program Manual GCG Package ver 7-UNIX. (575 Science Drive, Madison, Wisconsin 53711,1991).

  41. Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & Rutter, W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18, 5294–5299 (1979).

    Article  CAS  PubMed  Google Scholar 

  42. Kawasaki, E.S. In PCR protocols. A guide to methods and applications. (eds Innis A., Golfond, D. H., Sninsley J. J. & White T. J.) (Academic Press, 1990).

    Google Scholar 

  43. Sundin, O., Busse, H.G., Rogers, M.B., Gudas, L.J & Eichele, G. Region-specific expression in early chick and mouse embryos of Ghox-lab and Hox 1.6, vertebrate homeobox-containing genes related to Drosophila labial. Development 108, 47–58 (1990).

    CAS  PubMed  Google Scholar 

  44. Putt, F.A. Manual of Histopathological Staining Methods. 304–305 (John Wiley, New York, 1972).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rugarli, E., Lutz, B., Kuratani, S. et al. Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting. Nat Genet 4, 19–26 (1993). https://doi.org/10.1038/ng0593-19

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0593-19

This article is cited by

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