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The Journal of Neuroscience, March 3, 2004, 24(9):2277-2285; doi:10.1523/JNEUROSCI.4868-03.2004

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Cellular/Molecular
A Novel Role For Serum Response Factor in Neuronal Survival

Sandra H. Chang,¹ Steve Poser,² and Zhengui Xia^1,2

Departments of ¹Environmental and Occupational Health Sciences and ²Pharmacology, Graduate Program in Neurobiology and Behavior, Graduate Program in Molecular and Cell Biology, University of Washington, Seattle, Washington 98195-7234

Recent studies indicate that neuroprotection afforded by brain-derived neurotrophic factor (BDNF) is mediated by extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K). However, the mechanisms by which ERK and PI3K exert neuroprotection are not completely understood. Because ERK1/2 and PI3K both stimulate serum response element (SRE)-mediated gene expression, and serum response factor (SRF) is indispensable for SRE-mediated transcription, we investigated whether SRF contributes to ERK1/2 and PI3K neuroprotection. To accomplish this goal, we used an established experimental paradigm in which BDNF protects postnatal cortical neurons against both trophic deprivation and camptothecin-induced DNA damage. BDNF protection against camptothecin is mediated primarily by ERK1/2 activation, whereas its protection against trophic deprivation is mainly through stimulation of the PI3K pathway (Hetman et al., 1999). Here we demonstrate that expression of a wild-type SRF is sufficient to protect postnatal cortical neurons against camptothecin or trophic deprivation. Expression of a dominant-negative SRF partially reversed BDNF neuroprotection against both apoptotic insults. Moreover, the dominant-negative SRF inhibited neuroprotection against trophic withdrawal afforded by expression of a constitutive active PI3K. In addition, protection against camptothecin by expression of constitutive active mitogen-activated protein kinase kinase 1, an upstream kinase that activates ERK1/2, was also blocked by expression of the dominant-negative SRF. These data suggest that SRF is both necessary and sufficient for BDNF neuroprotection of cortical neurons against trophic deprivation and DNA damage. Our data provide a direct demonstration of a biological function of SRF in neurons and a novel downstream neuroprotective mechanism common to both ERK1/2 and PI3K pathways.

Key words: SRF; SRE; BDNF; PI3K; ERK1/2; neuronal survival; apoptosis; cortical neuron; CNS; transcription

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Received Oct 29, 2003; revised January 20, 2004; accepted January 20, 2004.

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