Mouse mutants with inherited defects of oligodendrocyte and Schwann cell function provide in vivo evidence that myelin-forming glial cells contribute to long-term axonal integrity. Loss of this supportive function in mice can occur even in the presence of intact myelin, as measured by rapid impulse propagation and the physical stability of myelin itself. Thus, glial support of myelinated axons emerges as a principal function of myelin-forming glial cells.
Oligodendroglial support of axonal integrity throughout adult life is relevant for any demyelinating disease. Axonal loss occurs in MS, but the causal relationship of acute inflammation, chronic demyelination, and axonal loss is difficult to solve. PLP or CNP-null mice show that progressive axonal loss can be caused by local dysfunction of oligoden-drocytes in the absence of overt inflammation and demyeli-nation. The molecular nature of this supportive function remains to be determined. Myelination itself appears to trigger this mutual dependency, as normally unmyelinated axons remain intact in the absence of glial support.
These considerations suggest that in human MS lesions, the widespread loss of myelin and functional oligodendro-cytes contributes to the described axonal pathology, including wallerian degeneration and persistent clinical disabilities. At least at later stages of the disease, the axonal pathology described in chronic demyelinated lesions (Bitsch et al., 2000; Bjartmar and Trapp, 2003) may correspond to the neu-ropathology of mouse mutants with noninflammatory myelin defects.
In several vertebrate species, the ensheathment of axons that emanates from retinal ganglion cells is by loose myelin (Easter et al., 1984; Fujita et al., 2001). These sheaths are ultrastructurally similar to myelin in some of the mutants described here and may represent a link between ensheath-ments by myelinating and nonmyelinating glia.
If glial cells provide local axonal support independent of the elaboration of myelin, this interaction may reflect a primary function of glial cells in vertebrate evolution. Although it is possible that myelinating glial cells have adopted a secondary support function for axons, it seems more reasonable to assume that the evolution of myelin in early vertebrates (Witkovsky, 1971; Agrawal et al., 1971; Bullock et al., 1984) was a recruitment of glial cells already functionally associated with axons (similar to non-myelin-forming Schwann cells), possibly to provide long-term axonal support.
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