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The Journal of Neuroscience, August 15, 1998, 18(16):6358-6369

Upregulation of a New Microglial Gene, mrf-1, in Response to Programmed Neuronal Cell Death and Degeneration

Shuuitsu Tanaka¹, Kazuhiko Suzuki¹, Masahiko Watanabe², Akira Matsuda³, Sigenobu Tone⁴, and Tatsuro Koike¹

¹ Molecular Neurobiology Laboratory, Graduate Program in Biological Sciences, Departments of ² Anatomy and ³ Ophthalmology, Faculty of Medicine, Hokkaido University, Sapporo 060-0810, Japan, and ⁴ Tokyo Metropolitan Institute of Medical Science, Tokyo 113-0021, Japan

Cerebellar granule neurons isolated from postnatal day 7 (P7) rats and grown in normal K⁺ medium begin to degenerate at approximately 4 d in vitro (DIV) and die. To search for genes upregulated in the process of neuronal cell death, differential hybridization was performed with subtracted cDNA probes and a cDNA library from 5 DIV. One of the genes isolated was microglial response factor-1 (mrf-1), which encoded a sequence of 177 amino acids with a single EF-hand calcium-binding motif. By Northern blots, the transcript was upregulated in cerebellar culture at 4 DIV, peaked at 6 DIV, and decreased at 7 DIV. Upregulation was also found when the apoptosis of granule cells was induced by replacing high K⁺ medium with normal K⁺ medium. However, when non-neuronal cells were thoroughly eliminated with aphidicolin, an antimitotic agent, the upregulation at 4-7 DIV did not occur. By immunocytochemistry, MRF-1 was detected at 5 DIV in OX-42-positive cells (microglia), and it exhibited an increase in response to granule cell death. MRF-1 levels in microglia purified from cerebral cortex also upregulated in the presence of 5 DIV granule cells. In the developing cerebellum in vivo, levels of mrf-1 mRNA transiently increased in the early postnatal stages, reaching a peak at P7 when cerebellar neurons and astrocytes undergo extensive apoptosis. In adult brain sections, MRF-1 was detected in the perikarya and processes of ramified/resting microglia, and peripheral motor nerve dissection prominently increased the expression in activated microglia surrounding injured central motoneurons. Therefore, mrf-1 appears to be one of the microglial genes that respond to neuronal cell death and degeneration.

Key words: microglia; neuron; degeneration; apoptosis; programmed cell death; gene expression

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18166358-12$05.00/0

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