Due to a spontaneously occurring recessive mutation, claw paw (clp) mice have peripheral hypomyelination, axon sorting deficits and abnormal limb posture. Because their phenotype is specific to the peripheral nervous system, these mice provide an attractive model for studying Schwann cell development and Schwann cell-axon interactions. On page 76 of this issue, Bermingham and colleagues have identified the molecular basis of this mutation as well as a new signaling molecule in peripheral nerve development.

The authors used positional cloning to localize the mutation to Lgi4, a member of the leucine-rich, glioma inactivated (Lgi) family of genes encoding putative secreted proteins of unknown function. They find that claw paw mice have a 225 base pair insertion in Lgi4, leading to a protein that lacks exon 4. Lgi4 is expressed primarily in Schwann cells in the peripheral nervous system. As suggested by its structure, the authors show that it is a secreted protein, but that the claw paw mutation causes it to be retained in the endoplasmic reticulum.Cultures containing neurons and Schwann cells from claw paw mice had reduced myelination and Schwann cell maturation, and conditioned media from cells expressing wild-type Lgi4 rescued these deficits, suggesting the claw paw phenotype results from reduced Lgi4 secretion. These results provide new insights into the signaling mechanisms involved in peripheral nerve development and may point to Lgi4 as a potential therapeutic target for stimulating myelination in injury or disease.