Published online before print June 13, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070648

Accepted for publication April 3, 2008.

Article

Egr-1 Regulates Expression of the Glial Scar Component Phosphacan in Astrocytes after Experimental Stroke

Heike Beck^*, Matthias Semisch^*, Carsten Culmsee, Nikolaus Plesnila, and Antonis K. Hatzopoulos^*¶@

From the Institute for clinical Molecular Biology and Tumor Genetics,* German Research Center for Environmental and Health,* Helmholtz Center Munich, Munich, Germany; the Institutes of Physiology and Surgical Research, the Department of Pharmacy, Laboratory of Biotechnology and Pharmaceutical Biology, and the Laboratory of Experimental Neurosurgery, Institute for Surgical Research, Ludwig-Maximilians-University, Munich, Germany; and the Department of Medicine, Division of Cardiovascular Medicine, and the Department of Cell and Developmental Biology,^¶ Vanderbilt University, Nashville, Tennessee

^@ To whom correspondence should be addressed. E-mail: antonis.hatzopoulos{at}vanderbilt.edu.

	Abstract

Ischemic brain injury causes tissue damage and neuronal death. The deficits can often be permanent because adult neurons fail to regenerate. One barrier to neuronal regeneration is the formation of the glial scar, a repair mechanism that is otherwise necessary to seal off necrotic areas. The process of gliosis has been well described, but the mechanisms regulating the robust production of scar components after injury remain poorly understood. Here we show that the early growth response 1 transcriptional factor (Egr-1, also called Krox24, Zif268, and NGFI-A) is expressed in astrocytes in the ventricular wall, corpus callosum, and striatum of normal mouse brain. After experimental stroke caused by permanent occlusion of the middle cerebral artery, Egr-1 was expressed long term in reactive astrocytes that accumulate around the injury site. Gain- and loss-of-function studies in primary astrocytes indicated that Egr-1 regulates the transcription of chondroitin sulfate proteoglycans genes, the main extracellular matrix proteins of the glial scar. Egr-1 bound to a site within the phosphacan promoter and transactivated its expression. Egr-1-deficient mice accumulated lower levels of phosphacan RNA and protein than wild-type mice after stroke, but there were no measurable differences in neurite outgrowth toward the infarct area between the two groups. Our findings suggest that Egr-1 is an important component of the transcriptional network regulating genes involved in gliosis after ischemic injury.