Nature Neuroscience 9, 76 - 84 (2005)
Published online: 11 December 2005; | doi:10.1038/nn1598
The claw paw mutation reveals a role for Lgi4 in peripheral nerve developmentJohn R Bermingham Jr1, Harold Shearin1, Jamie Pennington1, Jill O'Moore1, Martine Jaegle2, Siska Driegen2, Arend van Zon2, Aysel Darbas2, Ekim Özkaynak2, Elizabeth J Ryu3, 4, Jeffrey Milbrandt3
& Dies Meijer21
McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405, USA. 2
Department of Cell Biology & Genetics, Erasmus MC University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. 3
Department of Pathology and Immunology, Washington University, Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA. 4
Department of Psychiatry, Washington University, Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Correspondence should be addressed to John R Bermingham Jr jrbjr@po.mri.montana.edu or Dies Meijer d.meijer@erasmusmc.nl 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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