ACTIVATION OF P44 AND P42 MAP KINASES IS NOT ESSENTIAL FOR THE SURVIVAL OF RAT SYMPATHETIC NEURONS

We have examined whether activation of MAP kinases [or extracellular s ignal-regulated kinases (ERKs)] is required for the survival of rat sy mpathetic neurons by comparing the actions of three survival factors w hose survival-promoting actions can be blocked by neutralizing Fab fra gments to p21ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344 -350), nerve growth factor (NGF), the cytokines ciliary neurotrophic f actor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival w as accompanied by an intense (15- to 30-fold) and steady (>24 h) activ ation of p44 and p42 ERKs which waned rapidly (t(1/2) similar to 30 mi n) upon NGF withdrawal. However, concentrations of NGF that induced a weak (4- to 5-fold) stimulation of the ERKs were not sufficient to mai ntain long-term survival. Moreover, prolonged and intense stimulation of the ERKs by NGF for up to 15.5 h was unable to confer long-term sur vival, since withdrawal of NGF after this time resulted in neuronal de ath that was kinetically indistinguishable from the death of neurons t hat had not been exposed to NGF. By contrast, CNTF and LIF continued t o support survival for up to 3 days after eliciting only transient (<3 0 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTc AMP induced survival for several days without any measurable activatio n of the ERKs, Taken together, these data suggest that ERK activation per se is neither necessary nor sufficient for survival and that alter native pathways exist for effecting long-term survival of rat sympathe tic neurons.