A Novel Role for Serum Response Factor in Neuronal Survival

Abstract

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.