Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons.

Abstract

Abstract. Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signaltransducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in El2 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGFo dependent El2 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.

Retinal neuroprotection by growth factors: A mechanistic perspective

“…Ras activation supports the survival of some neurons following TFD [Borasio et al, 1993;Nobes and Tolkovsky, 1995]. Conversely, inhibition of the Ras/MEK/ ERK pathway by PD98059 does not induce sympathetic neuron cell death [Virdee and Tolkovsky, 1996], consistent with alternative survival pathways in neurons.…”

CRYP-2: A receptor-type tyrosine phosphatase selectively expressed by developing vertebrate neurons

“…ras activity is likely to be important in axon growth (Borasio et al, 1993;Boguski and McCormick, 1993 ) . Syp protein is concentrated in growth cones in E7 forebrain (J. Perron and J.L.B., unpub.…”

Cellular survival: a play in three Akts

“…Several studies have suggested that Ras and its downstream effectors Raf-MEK-MAPK are critical mediators of GF-induced survival in a number of different cell types (Borasio et al 1989(Borasio et al , 1993Nobes and Tolkovsky 1995). It is now clear that the Raf-MEK-MAPK cascade does under some circumstances promote cell survival (Xia et al 1995;Parrizas et al 1997;Bergmann et al 1998;Kurada and White 1998;Meier and Evan 1998;Anderson and Tolkovsky 1999;Bonni et al 1999;Shimamura et al 1999).…”