TrkB signalling inhibits p75-mediated apoptosis induced by nerve growth factor in embryonic proprioceptive neurons

Abstract

Neurotrophins mediate their effects by binding to members of the Trk family of receptor tyrosine kinases and the neurotrophin receptor p75 [1]. Whereas Trks are essential for the trophic effects of neurotrophins [1], p75 has distinct functions in different cells. For example, it enhances the survival response of certain neurons to nerve growth factor (NGF) [2], but mediates a cytotoxic response to NGF in certain other cell types and neurons [3] [4] [5] [6]. We investigated whether the p75-mediated responses to NGF can be modulated through the activation of different signalling pathways in the same neurons. Neurons of the embryonic trigeminal mesencephalic nucleus (TMN) are supported in culture by brain-derived neurotrophic factor (BDNF) and an unrelated neurotrophic factor, ciliary neurotrophic factor (CNTF), but not by NGF [7] [8] [9]. We found that NGF killed TMN neurons that were grown in the presence of CNTF; this effect of NGF was inhibited by anti-p75 antibodies and therefore occurred via a p75-dependent mechanism. NGF did not affect the survival of neurons grown in the presence of BDNF, and very low concentrations of BDNF inhibited NGF cytotoxicity. These results indicate that the activation of different signalling pathways in TMN neurons influences their susceptibility to p75-mediated NGF cytotoxicity.

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

“…In general, it seems that neurotrophins can only induce cell death through p75 in cells not expressing their specific Trk receptors (Bamji et al 1998;Yoon et al 1998). By contrast, coactivation of the appropriate Trk receptors inhibits neurotrophin-induced p75-mediated apoptosis, as demonstrated with cultured oligodendrocytes and neurons (Davey and Davies 1998). Trk activation can block p75-mediated cell death by several mechanisms.…”

A Novel p75NTR Signaling Pathway Promotes Survival, Not Death, of Immunopurified Neocortical Subplate Neurons

“…Ceramide in turn acts as a second messenger that activates apoptotic pathways in some cell types (Casaccia-Bonnefil et al, 1996;Hannun, 1996). In cells that express both p75NTR and a Trk, coactivation of the high-affinity Trk receptors has been found to suppress p75NTR activation of the ceramide pathway and apoptosis (Dobrowsky et al, 1995;Bamji et al, 1998;Davey and Davies, 1998;Yoon et al, 1998). By this model, the p75NTR apoptotic pathway is only activated by neurotrophins when the Trk receptor tyrosine kinase is not coactivated.…”

Dual role for p75NTR signaling in survival and cell death: Can intracellular mediators provide an explanation?

“…Due to the presence of death domain, cell death or apoptosis has been attributed as a cellular outcome of p75 NTR signaling (Rabizadeh and Bredesen, 1994). In this context, p75 NTR has been shown to induce apoptosis of cultured neonatal sympathetic neurons (Bamji et al, 1998), motor neurons (Sedel et al, 1999), sensory neurons (Barrett and Bartlett, 1994), oligodendrocytes (Casaccia-Bonnefil et al, 1996), and in neurons when Trk activation is reduced or absent (Davey and Davies, 1998). The intracellular region of p75 NTR that resembles the death domain, however, shows crucial structural differences compared to the tumor necrosis factor receptor (TNFR) death domain and does not self-associate or bind to the death -molecules such as FADD, TNF receptor associated protein death domain (TRADD), or receptor interacting protein (RIP; Nichols et al, 1998).…”