The mechanism of neuropathy in peripheral myelin protein 22 mice
Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated with peripheral neuropathy in mice and humans. PMP22 is produced mainly in Schwann cells in the peripheral nervous system where it is localised to compact myelin. The function of PMP22 is unclear but its low abundance makes it unlikely to be a structural myelin protein. I have studied the peripheral nerves of two different mouse models with alterations in the pmp22 gene. (1) The Trembler-J (Tr^J) mouse which has a point mutation [L16P] in the first transmembrane domain of PMP22. (2) PMPP22 overexpressing transgenic mice which have 7 (C22), 4 (C61) and 2 (C2) copies of the human PMP22 gene in addition to the mouse pmp22 gene. In the nerves of adult Tr^J mice there was considerable evidence of abnormal Schwann cell-axon interactions. Abnormal features were reproduced in the early stages of regeneration following crush injury. This demonstrates that the abnormalities are a result of an intrinsic abnormality of Tr^J Schwann cells and not secondary changes related to demyelination. In the initial stages of postnatal development the number of axons that were singly ensheathed was the same in all the mutants examined, indicating that PMP22 does not function in the initial enclosure of groups of axons and subsequent separation of single axons. All strains examined had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. Increasing the number of copies of PMP22 resulted in an increasing severity of phenotype. In C22 (7 copy) animals myelin formation was delayed or non-existent in many fibres whereas in C61 animals myelination initially appeared normal with abnormality appearing later in a small population of fibres. The C2 strain appeared relatively unaffected. It is concluded that PMP22 functions in the initiation of myelination and most probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities are most likely to result from defective interactions between the axon and the Schwann cell.