The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death

An increase in the level of the c-Jun transcription factor and of its phosphorylation has previously been shown to he essential for nerve growth factor (NGF) withdrawal induced apoptosis of rat sympathetic neurons (SCG), The Rho-like GTPascs Cdc42 and Rad are involved in the regulation of a number of cellular professes, including activation of the c-Jun NH(2)-terminal kinase (JNK) pathway, Therefore, we have investigated the role of these GTPases in this process, Overexpression of activated Rad or Cdc42 in SCG neurons maintained in the presence of NGF induced apoptosis, whereas expression of dominant negative mutants of Cdc42 or Rad blocked apoptosis following NGF withdrawal, Cdc42 activation produced an increase in the level of c-Jun and of its phosphorylation. Furthermore, Cdc42-induced death was prevented by coexpressing the c-Jun dominant negative FLAG Delta 169, Thus, Cdc42 appears to function as an initiator of neuronal cell death by activating a transcriptional pathway regulated by c-Jun.