The septin cytoskeleton is associated with distinct myelin structures of the central and peripheral nervous system

Rapid conduction of nerve impulses in the nervous system of higher vertebrates is made possible by ensheathment of nerve fibers by the specialized plasma membrane structure myelin. Consequently, failure of myelination or damage to the myelin sheath leads to severe pathology as seen in multiple sclerosis. During myelination oligodendrocytes and Schwann cells are challenged to build up and maintain a highly complex multilaminar plasma membrane structure. It is well-known that myelin membranes are divided into subdomains with distinct protein and lipid composition. Nevertheless, it is unclear how these domains are generated and then maintained throughout the adult. Especially the mechanisms of interaction between cytoskeleton elements and membrane structures in the developing and adult myelin sheath are still unknown. In this work, the interaction of the cytoskeleton protein septin(Sept6) and the myelin and lymphocyte protein MAL is demonstrated. Septins are enriched in myelin membranes which is unique for cytoskeleton elements. Most important, the loss of Sept6 in myelin is compensated by its closest homolog Sept11 which clearly points to a functional role of septins in the myelin compartment. A detailed analysis of the septin protein family in myelinating cells was performed here. It was shown that septins are coordinately regulated during differentiation and myelination in Schwann cells and oligodendrocytes. On the protein level particular septins were identified to be differentially enriched in myelin membranes. They form distinct stoechiometric complexes interacting also with actin. We propose that septin/myelin membrane complexes play an important role in myelination. Septins might be crucial in the formation and maintenance of myelin subdomains as well as in the transport of myelin components. In line with this, a possible site of interaction between Sept6 and MAL was identified in the Schwann cell cytoplasm. There, Sept6 and MAL might be important for sorting and trafficking processes crucial for the targeting of myelin components into the emerging and adult myelin sheath. Sept6-deficient mice, however, did not disclose alterations in myelin ultrastructure and protein composition besides the upregulation of Sept11. But, it is well-known that the septin cortex is very robust and that homologous isoforms might compensate for the loss of single septins. In line with this, it is shown here that myelinating Schwann cells tolerate the loss of Sept2, which might be due to such compensation mechanisms. The function of Sept7 in myelination could not be elucidated, since downregulation in in vitro myelinating cultures led to unspecific effects probably on cytokinesis and cell survival. Nevertheless, this first comprehensive study on septins in oligodendrocytes and Schwann cells generated valuable data critical for further analysis of septin function in myelin. This study provides insight into the composition of the septin cytoskeleton, its regulation during myelination and its interaction with myelin membranes. Understanding the role of the septin cytoskeleton in myelin formation and maintenance may reveal new insights in the mechanisms of myelination and remyelination in health and disease.