A Role for Transforming Growth Factor a as an Inducer of Astrogliosis

TGFa is a member of the epidermal growth factor (EGF) family with which it shares the same receptor, the EGF receptor (EGFR). Synthesis of TGFa and EGFR in reactive astrocytes developing after CNS insults is associated with the differentia- tive and mitogenic effects of TGFa on cultured astrocytes. This suggests a role for TGFa in the development of astrogliosis. We evaluated this hypothesis using transgenic mice bearing the human TGFa cDNA under the control of the zinc-inducible metallothionein promoter. Expression levels of glial fibrillary acidic protein (GFAP) and vimentin and morphological features of astrocytes were used as indices of astroglial reactivity in adult transgenic versus wild-type mice provided with ZnCl2 in their water for 3 weeks. In the striatum, the hippocampus, and the cervical spinal cord, the three CNS areas monitored, trans- genic mice displayed enhanced GFAP mRNA and protein levels and elevated vimentin protein levels. GFAP-immunoreactive astrocytes exhibited numerous thick processes and hypertro- phied somata, which are characteristic aspects of reactive astrocytes. Their number increased additionally in the striatum and the spinal cord, but no astrocytic proliferation was ob- served using bromodeoxyuridine immunohistochemistry. Nei- ther the morphology nor the number of microglial cells ap- peared modified. A twofold increase in phosphorylated EGFR was detected in the striatum and was associated with the immunohistochemical detection of numerous GFAP-positive astrocytes bearing the EGFR, suggesting a direct action of TGFa on astrocytes. Altogether, these results demonstrate that enhanced TGFa synthesis is sufficient to trigger astrogliosis throughout the CNS, whereas microglial metabolism is unaffected.