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The Journal of Neuroscience, February 1, 2001, 21(3):865-874

A Novel Role for Protein Tyrosine Phosphatase SHP1 in Controlling Glial Activation in the Normal and Injured Nervous System

Andrea Horvat¹, Franz-Werner Schwaiger¹, Gerhard Hager¹, Frank Bröcker¹, Robert Streif¹, Pjotr G. Knyazev², Axel Ullrich², and Georg W. Kreutzberg¹

¹ Department of Neuromorphology, Max-Planck-Institute of Neurobiology and ² Department of Molecular Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany

Tyrosine phosphorylation regulated by protein tyrosine kinases and phosphatases plays an important role in the activation of glial cells. Here we examined the expression of intracellular protein tyrosine phosphatase SHP1 in the 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 cortical lesion led to a massive upregulation of SHP1 in activated microglia and astrocytes, whereas the neuronal expression of SHP1 was not affected. In vitro experiments revealed that in astrocytes, SHP1 associates with epidermal growth factor (EGF)-receptor, whereas in microglia, SHP1 associates with colony-stimulating factor (CSF)-1-receptor. In postnatal and adult moth-eaten viable (me^v/me^v) mice, which are characterized by reduced SHP1 activity, a strong increase in reactive astrocytes, defined by GFAP immunoreactivity, was observed throughout the intact CNS, whereas neither the morphology nor the number of microglial cells appeared modified. Absence of ³[H]-thymidine-labeled nuclei indicated that astrocytic proliferation does not occur. In response to injury, cell number as well as proliferation of microglia were reduced in me^v/me^v mice, whereas the posttraumatic astrocytic reaction did not differ from wild-type littermates. The majority of activated microglia in mutant mice showed rounded and ameboid morphology. However, the regeneration rate after facial nerve injury in me^v/me^v mice was similar 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 injured CNS.

Key words: tyrosine phosphorylation; signal transduction; protein tyrosine phosphatase SHP1; peripheral nerve axotomy; facial nerve; hypoglossal nerve; sciatic nerve; direct cortical lesion; microglial proliferation; mutant moth-eaten viable mice

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Copyright © 2001 Society for Neuroscience  0270-6474/01/213865-10$05.00/0

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