Axoglial interactions underlie the clustering of ion channels and of cell adhesion molecules, regulate gene expression, and control cell survival. We report that Cnp1‐null mice, lacking expression of the myelin protein cyclic nucleotide phosphodiesterase (CNP), have disrupted axoglial interactions in the central nervous system (CNS). Nodal sodium channels (Nav) and paranodal adhesion proteins (Caspr) are initially clustered normally, but become progressively disorganized with age. These changes are characterized by mislocalized Caspr immunostaining, combined with a decrease of clustered Na⁺ channels, and occur before axonal degeneration and microglial invasion, both prominent in older Cnp1‐null mice. We suggest that CNP is a glial protein required for maintaining the integrity of paranodes and that disrupted axoglial signaling at this site underlies progressive axonal degeneration, observed later in the CNS of Cnp1‐null mice. © 2005 Wiley‐Liss, Inc.