A role for transforming growth factor alpha as an inducer of astrogliosis

TGF alpha is a member of the epidermal growth factor (EGF) family with whic h it shares the same receptor, the EGF receptor (EGFR). Synthesis of TGF al pha and EGFR in reactive astrocytes developing after CNS insults is associa ted with the differentiative and mitogenic effects of TGFa on cultured astr ocytes. This suggests a role for TGF alpha in the development of astroglios is. We evaluated this hypothesis using transgenic mice bearing the human TG F alpha cDNA under the control of the zinc-inducible metallothionein promot er. Expression levels of glial fibrillary acidic protein (GFAP) and vimenti n and morphological features of astrocytes were used as indices of astrogli al reactivity in adult transgenic versus wild-type mice provided with ZnCl2 in their water for 3 weeks. In the striatum, the hippocampus, and the cerv ical spinal cord, the three CNS areas monitored, transgenic mice displayed enhanced GFAP mRNA and protein levels and elevated vimentin protein levels. GFAP-immunoreactive astrocytes exhibited numerous thick processes and hype rtrophied somata, which are characteristic aspects of reactive astrocytes. Their number increased additionally in the striatum and the spinal cord, bu t no astrocytic proliferation was observed using bromodeoxyuridine immunohi stochemistry. Neither the morphology nor the number of microglial cells app eared modified. A twofold increase in phosphorylated EGFR was detected in t he striatum and was associated with the immunohistochemical detection of nu merous GFAP-positive astrocytes bearing the EGFR, suggesting a direct actio n of TGF alpha on astrocytes. Altogether, these results demonstrate that en hanced TGF alpha synthesis is sufficient to trigger astrogliosis throughout the CNS, whereas microglial metabolism is unaffected.