Neural differentiation and the attenuated heat shock response

Differentiation of neural progenitor cells of neuroblastoma, pheochromocytoma, and surrogate stem cell lineages from a state resembling stem cells to a state resembling neurons is accompanied by a marked attenuation in induction of the heat shock protein 70 promoter driven-luciferase reporter gene, and induction of the reporter gene in primary embryonic neurons from hippocampus, cortex, and spinal cord is lower still when compared to the differentiated cells. Neural specificity of this phenotype is demonstrated by a negative correlation of hsp70-reporter gene expression and neurite extension under various experimental conditions. Analysis of biochemical events involved in induction of the heat shock response (HSR) reveal a blunted activation of HSF1 DNA-binding activity, and decreased induction of the mRNAhsp70 and the 72 kDa HSP70 protein. Immunocytochemical staining for HSP70 demonstrates a cytoplasmic staining pattern; heat shock greatly increased the HSP70 staining intensity in the undifferentiated cells and less so in the differentiated cells. Vulnerability of the differentiated cells towards the oxidizer, arsenite, and the excitotoxic glutamate/glycine is demonstrated by the dose-dependent cytotoxic effects of these agents on cell viability and activation of caspase 3/7. Importantly, conditioning heat shock as well as increased expression of HSP70 by gene transfer conferred protection against such cytotoxicity. Together, our results show that neural differentiation is associated with a decreased induction of the heat shock response and an increased vulnerability to stress induced pathologies and death.