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The claw paw mutation reveals a role for Lgi4 in peripheral nerve development

Nature Neuroscience volume 9, pages 7684 (2006) | Download Citation

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Abstract

Peripheral nerve development results from multiple cellular interactions between axons, Schwann cells and the surrounding mesenchymal tissue. The delayed axonal sorting and hypomyelination throughout the peripheral nervous system of claw paw (clp) mutant mice suggest that the clp gene product is critical for these interactions. Here we identify the clp mutation as a 225-bp insertion in the Lgi4 gene. Lgi4 encodes a secreted and glycosylated leucine-rich repeat protein and is expressed in Schwann cells. The clp mutation affects Lgi4 mRNA splicing, resulting in a mutant protein that is retained in the cell. Additionally, siRNA-mediated downregulation of Lgi4 in wild-type neuron–Schwann cell cocultures inhibits myelination, whereas exogenous Lgi4 restores myelination in clp/clp cultures. Thus, the abnormalities observed in clp mice are attributable to the loss of Lgi4 function, and they identify Lgi4 as a new component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.

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Acknowledgements

We thank D. Krajacich for technical assistance, as well as the undergraduate summer students who worked on this project at the McLaughlin Research Institute: C. Schedl, M. Chen, S. Brauer, J. Anspach-Hanson and B. Cook. We also thank C. Ebeling for assistance with LI-COR analysis; S.S. Scherer for providing the PLP plasmid; N. Jenkins, N. Copeland, J. Chan and T. Watkins for protocols and advice; and E. Dzierzak for critical reading of the manuscript. This work was funded by the National Institute of Neurological Diseases and Stroke (NINDS) grant NS40751 and Muscular Dystrophy Association grant 3476 to J.R.B. Jr.; NINDS grants NS049087 and NS40745 to J.M.; and by grants from the Nederlandse Organisatie van Wetenschappelijk Onderzoek (NWO; ZonMW 903-42-195 and 901-01-205) to D.M.

Author information

Affiliations

  1. McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405, USA.

    • John R Bermingham Jr
    • , Harold Shearin
    • , Jamie Pennington
    •  & Jill O'Moore
  2. Department of Cell Biology & Genetics, Erasmus MC University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

    • Martine Jaegle
    • , Siska Driegen
    • , Arend van Zon
    • , Aysel Darbas
    • , Ekim Özkaynak
    •  & Dies Meijer
  3. Department of Pathology and Immunology, Washington University, Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.

    • Elizabeth J Ryu
    •  & Jeffrey Milbrandt
  4. Department of Psychiatry, Washington University, Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.

    • Elizabeth J Ryu

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to John R Bermingham Jr or Dies Meijer.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Results of the C57BL/6J-clp/+ X BALB/c backcross.

  2. 2.

    Supplementary Fig. 2

    Fine mapping of the clp candidate region.

  3. 3.

    Supplementary Fig. 3

    BAC transgene complementation of Lgi4clp.

  4. 4.

    Supplementary Fig. 4

    Mechanism of Lgi4clp exon exclusion.

  5. 5.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nn1598

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