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Previous Article | Next Article
The Journal of Neuroscience, February 15, 2001, 21(4):1257-1264
Regulation of Neuregulin Expression in the Injured Rat Brain and Cultured Astrocytes
Yoshihito Tokita1, Hiroomi Keino1, Fumiko Matsui1, Sachiko Aono1, Hiroshi Ishiguro2, Shigeki Higashiyama3, and Atsuhiko Oohira1 1 Department of Perinatology, Institute for Developmental Research, Kasugai, Aichi 480-0392, Japan, 2 Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan, and 3 Department of Biochemistry, School of Allied Health Science, Osaka University Medical School, Suita, Osaka 565-0871, Japan
In this report, we investigated whether reactive astrocytes produce neuregulins (glial growth factor 2/heregulin/acetylcholine receptor-inducing activity or neu differentiation factor) and its putative receptors, ErbB2 and ErbB3 tyrosine kinases, in the injured CNS in vivo. Significant immunoreactivities with anti-neuregulin, anti-ErbB2, and anti-ErbB3 antibodies were detected on astrocytes at the injured site 4 d after injury to the adult rat cerebral cortex. To elucidate the mechanisms for the upregulation of neuregulin expression in astrocytes, primary cultured astrocytes were treated with certain reagents, including forskolin, that are known to elevate the intracellular level of cAMP and induce marked morphological changes in astrocytes. Western blot analysis showed that the expression of a 52 kDa membrane-spanning form of a neuregulin protein was enhanced in cultured astrocytes after administration of forskolin. The upregulation of glial fibrillary acidic protein was also observed in astrocytes treated with forskolin. In contrast, inactivation of protein kinase C because of chronic treatment with phorbol ester 12-O-tetradecanoyl phorbol 13-acetate downregulated the expression of the 52 kDa isoform, although other splice variants with apparent molecular sizes of 65 and 60 kDa were upregulated. These results suggest that the enhancement of neuregulin expression at injured sites is induced, at least in part, by elevation in intracellular cAMP levels and/or a protein kinase C signaling pathway. The neuregulin expressed on reactive astrocytes may stimulate their proliferation and support the survival of neurons surrounding cortical brain wounds in vivo.
Key words: neuregulin; ErbB2; ErbB3; forskolin; astrocyte; trauma; protein kinase A
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141257-08$05.00/0
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