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The Journal of Neuroscience, July 15, 2002, 22(14):5879-5888

Serial Analysis of Gene Expression Identifies Metallothionein-II as Major Neuroprotective Gene in Mouse Focal Cerebral Ischemia

George Trendelenburg¹, Konstantin Prass¹, Josef Priller¹, Krisztian Kapinya¹, Andreas Polley², Claudia Muselmann¹, Karsten Ruscher¹, Ute Kannbley¹, Armin O. Schmitt³, Stefanie Castell¹, Frank Wiegand⁴, Andreas Meisel¹, André Rosenthal^{2, 3, 5}, and Ulrich Dirnagl¹

¹ Department of Neurology, Charité, Humboldt University Berlin, D-10098 Berlin, Germany, ² Department of Genome Analysis, Institute of Molecular Biotechnology, D-07745 Jena, Germany, ³ metaGen Pharmaceuticals GmbH, D-13347 Berlin, Germany, ⁴ Janssen Cilag AG, D-41470 Neuss, Germany, and ⁵ Department of Biology, Friedrich Schiller University, D-07743 Jena, Germany

We applied serial analysis of gene expression (SAGE) to study differentially expressed genes in mouse brain 14 hr after the induction of focal cerebral ischemia. Analysis of >60,000 transcripts revealed 83 upregulated and 94 downregulated transcripts (more than or equal to eightfold). Reproducibility was demonstrated by performing SAGE in duplicate on the same starting material. Metallothionein-II (MT-II) was the most significantly upregulated transcript in the ischemic hemisphere. MT-I and MT-II are assumed to be induced by metals, glucocorticoids, and inflammatory signals in a coordinated manner, yet their function remains elusive. Upregulation of both MT-I and MT-II was confirmed by Northern blotting. MT-I and MT-II mRNA expression increased as early as 2 hr after 2 hr of transient ischemia, with a maximum after 16 hr. Western blotting and immunohistochemistry revealed MT-I/-II upregulation in the ischemic hemisphere, whereas double labeling demonstrated the colocalization of MT with markers for astrocytes as well as for monocytes/macrophages. MT-I- and MT-II-deficient mice developed approximately threefold larger infarcts than wild-type mice and a significantly worse neurological outcome.

For the first time we make available a comprehensive data set on brain ischemic gene expression and underscore the important protective role of metallothioneins in ischemic damage of the brain. Our results demonstrate the usefulness of SAGE to screen functionally relevant genes and the power of knock-out models in linking function to expression data generated by high throughput techniques.

Key words: differential gene expression; knock-out mice; screening approach; serial analysis of gene expression (SAGE); stroke; focal cerebral ischemia

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22145879-10$05.00/0

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