Proliferating Schwann cells, the glial cells of the peripheral nervous system, are a prominent feature during early development and after damage to peripheral nerves. Altered Schwann cell proliferation is also associated with diseases and pathological states including inherited peripheral neuropathies, peripheral nerve tumors, and peripheral neuropathies secondary to diabetes, cancer chemotherapeutic agents, or toxins. To gain more insight into the molecular processes governing Schwann cell proliferation in health and disease, we examined the Schwann cell cycle and its regulation in vivo. Methods: We have examined the expression, regulation, and localization of cyclins, cyclin-dependent kinases (cdk), and cell cycle inhibitors in Schwann cells of developing and adult peripheral nerves using immunohistochemistry. In addition, we used appropriate mutant mice to examine the functional requirement for the respective cell cycle proteins in Schwann cell proliferation. Results: Proliferating Schwann cells during development express cyclin D1 in the cytoplasm. After injury, cyclin D1 becomes localized to the nuclei of proliferating Schwann cells. Cyclin D1-deficient animals revealed that developmentally regulated proliferation is not affected by the absence of cyclin D1, whereas injury-induced proliferation is impaired. We further found that the cell cycle inhibitor p21 appears first in the cytoplasm of Schwann cells at postnatal day 7 when most cells have already ceased dividing. After nerve injury, however, p21 is localized mainly in nuclei of dedifferentiated Schwann cells. Consistently, p21-deficient Schwann cells do not undergo proper growth arrest in later phases of nerve development. In contrast, after nerve injury, nuclear p21 is required for correct cell cycle control at the peak of Schwann cell proliferation. We next investigated the requirements for cdk2, 4, and 6 during Schwann cell proliferation. We show that only cdk2 and 4 are expressed in peripheral nerves. Our data from cdk-deficient mice indicate that postnatal Schwann cell proliferation is abolished in the absence of cdk4 but not in the absence of cdk2 or 6. Conclusions: We find that distinct components of the cell cycle machinery that regulate Schwann cell proliferation during development differ fundamentally from those activated following nerve injury or in peripheral neuropathies.

Username
Password