Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes.

Previous studies in this laboratory have shown that the SH-2 domain-containing protein tyrosine phosphatase SHP-1 is expressed in CNS glia and functions to modulate cytokine activities in these cells. The present study demonstrates that SHP-1 is expressed within multiple regions of the CNS in vivo, especially in white matter. Interestingly, we show that mice genetically lacking in SHP-1 (motheaten mice) in the CNS displayed dysmyelination. We therefore examined the expression of SHP-1 in the myelin-forming oligodendrocytes. Oligodendrocytes present in either mixed glial cultures or pure cultures expressed high levels of SHP-1 in the cytoplasm of cell bodies and processes. Oligodendrocytes isolated from motheaten mice did not express SHP-1. To test possible functions for SHP-1 in oligodendrocytes in controlling cytokine signaling, we compared the responsiveness of oligodendrocytes isolated from either motheaten or normal littermate mice with IL-6. IL-6 induced higher levels of STAT3 phosphorylation and STAT3-responsive c-fos gene expression in pure oligodendrocyte cultures of motheaten compared with normal littermate mice. These studies demonstrate that oligodendrocytes express SHP-1 and that SHP-1 functions to control IL-6 signaling. SHP-1 may therefore be a critical regulator of oligodendrocyte differentiation in response to IL-6 family cytokines. Further, these findings may relate to dysmyelination in mice lacking SHP-1.