Progression of Wallerian degeneration and axon regeneration after peripheral nerve injury (PNI). A single axon with associated myelinating Schwann cells is shown. Although myelin phagocytosis and degeneration occurs within the basal lamina (purple), the basal lamina is shown only in panel 1 for clarity. 1. The endoneurium of an uninjured nerve consists of axons, associated Schwann cells (myelinating and nonmyelinating), and resident, inactivated macrophages. 2. Soon after PNI, denervated myelinating Schwann cells release their myelin. These Schwann cells then proliferate within their basal lamina tubes, produce cytokines/trophic factors, and phagocytose detached debris. In addition, the reaction within the neuron cell body begins: this is characterized by cell soma hypertrophy, displacement of the nucleus to an eccentric position, and dissolution of Nissl bodies. 3. Wallerian degeneration is well underway within a week of injury. Soluble factors produced by Schwann cells and injured axons activate resident macrophages and lead to recruitment of hematogenous macrophages. The activated macrophages clear myelin and axon debris efficiently, and produce factors that facilitate Schwann cell migration and axon regeneration. 4. After a lag period, injured axons form a growth cone and begin to regenerate along bands of Büngner formed by Schwann cells. These tubes provide a permissive growth environment and guide extending axons towards potential peripheral targets. Schwann cells that have been chronically denervated (e.g., for a few months) are less supportive of regrowth and are more likely to undergo apoptosis. 5. If the axon is able to traverse the injury site, and its environment supports its growth along the entire distal stump, then the axon can connect with peripheral targets. Although myelinating Schwann cells do remyelinate the regenerated portion of axon, the myelin is thinner and the nodal length is shorter than in the uninjured portion of axon. See text for references.