A novel role for protein tyrosine phosphatase SHP1 in controlling glial activation in the normal and injured nervous system

Tyrosine phosphorylation regulated by protein tyrosine kinases and phosphat ases plays an important role in the activation of glial cells. Here we exam ined the expression of intracellular protein tyrosine phosphatase SHP1 in t he normal and injured adult rat and mouse CNS. Our study showed that in the intact CNS, SHP1 was expressed in astrocytes as well as in pyramidal cells in hippocampus and cortex. Axotomy of peripheral nerves and direct cortica l lesion led to a massive upregulation of SHP1 in activated microglia and a strocytes, whereas the neuronal expression of SHP1 was not affected. In vit ro experiments revealed that in astrocytes, SHP1 associates with epidermal growth factor (EGF)-receptor, whereas in microglia, SHP1 associates with co lony-stimulating factor (CSF)-1-receptor. In postnatal and adult moth-eaten viable (me(v)/me(v)) mice, which are characterized by reduced SHP1 activit y, a strong increase in reactive astrocytes, defined by GFAP immunoreactivi ty, was observed throughout the intact CNS, whereas neither the morphology nor the number of microglial cells appeared modified. Absence of (3)[H]-thy midine-labeled nuclei indicated that astrocytic proliferation does not occu r. In response to injury, cell number as well as proliferation of microglia were reduced in me(v)/me(v) mice, whereas the posttraumatic astrocytic rea ction did not differ from wild-type littermates. The majority of activated microglia in mutant mice showed rounded and ameboid morphology. However, th e regeneration rate after facial nerve injury in me(v)/me(v) mice was simil ar to that in wild-type littermates. These results emphasize that SHP1 as a part of different signaling pathways plays an important role in the global regulation of astrocytic and microglial activation in the normal and injur ed CNS.