cyclin-d1 and Wallerian-Degeneration

Neurons regulate Schwann cell proliferation, but little is known about the molecular basis of this interaction. We have examined the possibility that cyclin D1 is a key regulator of the cell cycle in Schwann cells. Myelinating Schwann cells express cyclin D1 in the perinuclear region, but after axons are severed, cyclin D1 is strongly upregulated in parallel with Schwann cell proliferation and translocates into Schwann cell nuclei. During development, cyclin D1 expression is confined to the perinuclear region of proliferating Schwann cells and the analysis of cyclin D1-null mice indicates that cyclin D1 is not required for this type of Schwann cell proliferation. As in the adult, injury to immature peripheral nerves leads to translocation of cyclin D1 to Schwann cell nuclei and injury-induced proliferation is impaired in both immature and mature cyclin D1-deficient Schwann cells. Thus, our data indicate that the molecular mechanisms regulating proliferation of Schwann cells during development or activated by axonal damage are fundamentally different.

Topics: Aging; Animals; Animals, Newborn; Cell Compartmentation; Cell Differentiation; Cell Division; Cell Nucleus; Cells, Cultured; Cyclin D1; Cytoplasm; Gene Expression Regulation; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Sheath; Nerve Crush; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Rats, Inbred Strains; Schwann Cells; Sciatic Nerve; Wallerian Degeneration

Sciatic nerve axons in cyclin D1 knockout mice develop normally, become properly ensheathed by Schwann cells, and appear to function normally. However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited. The mitotic block is Schwann cell autonomous and developmentally regulated. Rescue analysis (by "knockin" of cyclin E) indicates that D1 protein, rather than regulatory elements of the D1 gene, provides the essential Schwann cell function. Genetic inhibition of the Schwann cell cycle shows that neuronal responses to nerve injury are surprisingly independent of Schwann cell mitotic responses. Even axonal regrowth into the distal zone of a nerve crush injury is not markedly impaired in cyclin D1-/- mice.

Topics: Animals; Cell Division; Cells, Cultured; Cellular Senescence; Cyclin D1; Cyclin E; Ganglia, Spinal; Gene Expression Regulation, Developmental; Genes, Switch; Mice; Mice, Knockout; Mitosis; Nerve Regeneration; Phenotype; Rats; Reference Values; Schwann Cells; Wallerian Degeneration