Following nerve injury, Schwann cells distal to the site of injury down-regulate genes associated with myelination. We hypothesized that at least some of these alterations were due to the loss of ongoing axon:Schwann cell homeostatic signals, as opposed to loss of physical contact and/or inflammatory responses. To directly test this hypothesis, we perturbed axonal physiology by selectively blocking fast axonal transport via locally cooling the sciatic nerve to 5-8 degrees C (a cold block). Immunostaining with the monoclonal antibody ED1, which recognizes mononuclear phagocytic cells, demonstrated that macrophages did not invade the cold-blocked nerve, indicating the lack of an inflammatory response. Morphological studies demonstrated that the nerve distal to the cold block showed no signs of Wallerian degeneration, with maintenance of normal axon and myelin profiles, and confirmed the absence of invading macrophages. Thus, any effects of a cold-block treatment were not likely due to inflammatory responses or to loss of physical contact between axons and Schwann cells. To determine whether this treatment affected Schwann cell phenotype, we examined expression of the major myelin protein P0, and p75 NGF receptor, both of which are regulated as a function of axon:Schwann cell interactions. Levels of p75 NGF receptor mRNA were unaffected by the cold block, while p75 NGF receptor protein levels were increased in the region of the nerve immediately adjacent to the cold block, presumably reflecting protein accumulation as a consequence of the block to fast axonal transport. In contrast, levels of P0 mRNA were decreased in the distal nerve in a fashion that indicated modulation of Schwann cell phenotype as a function of local axonal microenvironment. These data therefore suggest that P0 and p75 NGF receptor are regulated as a function of two different aspects of Schwann cell:axon communication. Furthermore, these data demonstrate that the presence of axon:Schwann cell contact alone is insufficient to maintain Po gene expression and indicate that at least some myelin-specific Schwann cell responses are dependent upon ongoing biochemical signals generated by the axon and maintained by fast axonal transport.