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Disruption of the mouse L1 gene leads to malformations of the nervous system

Nature Genetics volume 17, pages 346–349 (1997)Cite this article

Abstract

The adhesion molecule L1 is a member of the immunoglobulin super-family1. L1 is involved in various recognition processes in the CMS and PNS2–3, and binding to L1 can activate signal transduction pathways4,5. Mutations in the human L1 gene are associated with a variable phenotype, including mental retardation and anomalous development of the nervous system, referred to as ‘CRASH’ (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus)6. We generated an animal model of these conditions by gene targeting. Mutant mice were smaller than wild-type and were less sensitive to touch and pain, and their hind-legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Non-myelinating Schwann cells formed processes not associated with axons and showed reduced association with axons. In vitro, neurite outgrowth on an L1 substrate and fasciculation were impaired. The mutant mouse described here will help to elucidate the functions of L1 in the nervous system and how these depend on genetic influences.

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References

  1. Moos, M. et al. Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature. 334, 701–703 (1988).

    Article  CAS  Google Scholar 

  2. Kadmon, G. & Altevogt, P. The cell adhesion molecule L1: species- and cell-type-dependent multiple binding mechanisms. Differentiation. 61, 143–150 (1997).

    Article  CAS  Google Scholar 

  3. Martini, R. Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. J. Neumcytol. 23, 1–28 (1994).

    Article  CAS  Google Scholar 

  4. Doherty, P., Smith, P. & Walsh, F.S. Shared cell adhesion molecule (CAM) homology domains point to CAMs signalling via FGF receptors. Perspect. Dev. Neurobiol. 4, 157–168 (1996).

    CAS  PubMed  Google Scholar 

  5. Maness, P.P., Beggs, H.E., Klinz, S.G. & Morse, W.R. Selective neural cell adhesion molecule signaling by Src family tyrosine kinases and tyrosine phosphatases. Perspect Dev. Neurobiol. 4, 169–181 (1996).

    CAS  PubMed  Google Scholar 

  6. Fransen, E. et al. CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. Eur. J. Hum. Genet. 3, 273–284 (1995).

    Article  CAS  Google Scholar 

  7. Sadoul, K., Sadoul, R., Faissner, A. & Schachner, M. Biochemical characterization of different molecular forms of the neural cell adhesion molecule L1. J. Neurochem. 50, 510–521 (1988).

    Article  CAS  Google Scholar 

  8. Mah, C., Suissa, A. & Anisman, H. Dissociation of antinociception and escape deficits induced by stress in mice. J. Comp. Physiol. Psychol. 94, 1160–1171 (1980).

    Article  Google Scholar 

  9. Schrander-Stumpel, C. et al. Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): clinical review with six additional families. Am. J. Med. Genet. 57, 107–116 (1995).

    Article  CAS  Google Scholar 

  10. Fransen, E., Van Camp, G & Willems, P.J. The clinical spectrum of mutations in L1, a neurbnal cell adhesion molecule. Am. J. Med. Genet. 64, 73–77 (1996).

    Article  CAS  Google Scholar 

  11. Ramanathan, R., Wilkemeyer, M.F., Mittal, B., Perides, G. & Charness, M.E. Alcohol inhibits cell-cell adhesion mediated by human L1. J. Cell Biol. 133, 381–390 (1996).

    Article  CAS  Google Scholar 

  12. Fischer, G., Kunemund, V. & Schachner, M. Neurite outgrowth patterns in cerebellar microexplant cultures are affected by antibodies to the cell surface glycoprotein L1. J. Neurosci. 6, 605–612 (1986).

    Article  CAS  Google Scholar 

  13. Stallcup, W.B. & Beasley, L. Involvement of the nerve growth factor–inducible large external glycoprotein (NILE) in neurite fasciculation in primary cultures of rat brain. Proc. Nat. Acad. Sci. USA 82, 1276–1280 (1985).

    Article  CAS  Google Scholar 

  14. Lindner, J., Rathjen, F.G. & Schachner, M. L1 mono- and polyclonal antibodies modify cell migration in early postnatal mouse cerebellum. Nature. 305, 427–430 (1983).

    Article  CAS  Google Scholar 

  15. Miura, M., Asou, H., Kobayashi, M. & Uyemura, K. Functional expression of a full-length cDNA coding for rat neural cell adhesion molecule L1 mediates homophilic intercellular adhesion and migration of cerebellar neurons. J. Biol. Chem. 267, 10752–10758 (1992).

    CAS  PubMed  Google Scholar 

  16. Holm, J. et al. Structural features of a close homologue of L1 (CHL1) in the mouse: a new member of the L1 family of neural recognition molecules. Eur. J. Neurosci. 8, 1613–1629 (1996).

    Article  CAS  Google Scholar 

  17. Seilheimer, B., Persohn, E. & Schachner, M. Antibodies to the L1 adhesion molecule inhibit Schwann cell ensheathment of neurons in vitro. J. Cell Biol. 109, 3095–3103 (1989).

    Article  CAS  Google Scholar 

  18. Williams, E.J., Furness, J., Walsh, F.S. & Doherty, P. Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron. 13, 583–594 (1994).

    Article  CAS  Google Scholar 

  19. Appel, F., Holm, J., Conscience, J.F. & Schachner, M. Several extracellular domains of the neural cell adhesion molecule L1 are involved in neurite outgrowth and cell body adhesion. J. Neurosci. 13, 4764–4775 (1993).

    Article  CAS  Google Scholar 

  20. Bixby, J.L. & Jhabvala, P. Extracellular matrix molecules and cell adhesion molecules induce neurites through different mechanisms. J. Cell Biol. 111, 2735–2732 (1990).

    Article  Google Scholar 

  21. Lemmon, V., Farr, K.L. & Lagenaur, C. L1-mediated axon outgrowth occurs via a homophilic binding mechanism. Neuron. 2, 1597–1603 (1989).

    Article  CAS  Google Scholar 

  22. Reis, L.F.L., Ruffner, H., Stark, G., Aguet, M. & Weissmann, C. Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes. EMBO J. 13, 4798–4806 (1994).

    Article  CAS  Google Scholar 

  23. Appel, F. et al. Identification of the border between fibronectin type III homologous repeats 2 and 3 of the neural cell adhesion molecule L1 as a neurite outgrowth promoting and signal transducing domain. J. Neurobiol. 28, 297–312 (1995).

    Article  CAS  Google Scholar 

  24. Klinz, S.G., Schachner, M. & Maness, P.F. L1 and N-CAM antibodies trigger protein phosphatase activity in growth cone-enriched membranes. J. Neurochem. 65, 84–95 (1995).

    Article  CAS  Google Scholar 

  25. Martini, R., Zielasek, J., Toyka, K.V., Giese, K.P. & Schachner, M. Protein zero (PO)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nature Genet. 11, 281–286 (1995).

    Article  CAS  Google Scholar 

  26. Martini, R., Mohajeri, M.H., Kasper, S., Giese, K.P. & Schachner, M. Mice doubly deficient in the genes for PO and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J. Neurosci. 15, 4488–4495 (1995).

    Article  CAS  Google Scholar 

  27. Lagenaur, C. & Lemmon, V., L1-like molecule, the 8D9 antigen, is a potent substrate for neurite extension. Proc. Natl. Acad. Sci. USA. 84, 7753–7757 (1987).

    Article  CAS  Google Scholar 

  28. Constam, D.B., Schmid, P., Aguzzi, A., Schachner, M. & Fontana, A. Transient production of TGF-P2 by postnatal cerebellar neurons and its effect on neuroblast proliferation. Eur. J. Neurosci. 6, 766–778 (1994).

    Article  CAS  Google Scholar 

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Author notes

  1. Ned Mantei: Correspondence should be addressed to N.M.

Authors and Affiliations

  1. Department of Neurobiology, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093, Zürich, Switzerland

    Miriam Dahme, Udo Bartsch, Rudolf Martini, Brigitte Anliker, Melitta Schachner & Ned Mantei

  2. Developmental Neurobiology Section, Department of Neurology, University of Würzburg, Josef-Schneider-Strasse 11, D-97080, Wurzburg, Germany

    Rudolf Martini

  3. ZentrumfurMolekulareNeurobiologie, Hamburg University, Martinistrasse 52, D-20246, Hamburg, Germany

    Melitta Schachner

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  1. Miriam Dahme
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Correspondence to Ned Mantei.

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Dahme, M., Bartsch, U., Martini, R. et al. Disruption of the mouse L1 gene leads to malformations of the nervous system. Nat Genet 17, 346–349 (1997). https://doi.org/10.1038/ng1197-346

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