Egr-1 regulates expression of the glial scar component phosphacan in astrocytes after experimental stroke.
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.
Institute for Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, Helmholtz Center Munich, Munich, Germany.
Heike
H
Beck
Matthias
M
Semisch
Carsten
C
Culmsee
Nikolaus
N
Plesnila
Antonis K
AK
Hatzopoulos
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5