We have previously reported CNS and locomotor deficits in KCC3 knockout mice, an animal model of agenesis of the corpus callosum associated with peripheral neuropathy (ACCPN) [Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.B., Prevost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F.Q., Mercado, A., Siesser, W.B., George, A.L., Jr., McDonald, M.P., Bouchard, J.P., Mathieu, J., Delpire, E., Rouleau, G.A., 2002. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat. Genet. 32, 384-392]. To assess the role of KCC3 in peripheral axon and/or myelin development and maintenance, we determined its expression and performed a detailed morphometric analysis of sciatic nerves. Sciatic nerves of juvenile wild-type mice, but not of adult, express KCC3. In the knockout, Schwann cell/myelin development appears normal at P3, but axons are swollen. At P8 and into P30, some fibers accumulate fluid periaxonally. These initial swelling pathologies are followed by axon and myelin degeneration in adult nerves, leading to reduction in nerve conduction velocity. Mutant mice also exhibit decreased sensitivity to noxious pain. This evidence for fluid-related axonopathy, which ultimately result in neurodegeneration, implicates cell volume regulation as a critical component of peripheral nerve maintenance.