NGF and Neurotrophin-3 Both Activate TrkA on Sympathetic Neurons but Differentially Regulate Survival and Neuritogenesis

Abstract

In this report we examine the biological and molecular basis of the control of sympathetic neuron differentiation and survival by NGF and neurotrophin-3 (NT-3). NT-3 is as efficient as NGF in mediating neuritogenesis and expression of growth-associated genes in NGF-dependent sympathetic neurons, but it is 20–40fold less efficient in supporting their survival. Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity. At similar acute levels of TrkA activation, NT-3 still mediates neuronal survival two- to threefold less well than NGF. However, a mutant NT-3 that activates TrkC, but not TrkA, is unable to support sympathetic neuron survival or neuritogenesis, indicating that NT3–mediated TrkA activation is necessary for both of these responses. On the basis of these data, we suggest that NGF and NT-3 differentially regulate the TrkA receptor both with regard to activation time course and downstream targets, leading to selective regulation of neuritogenesis and survival. Such differential responsiveness to two ligands acting through the same Trk receptor has important implications for neurotrophin function throughout the nervous system.

Nerve Growth Factor- and Neurotrophin-3-Induced Changes in Nociceptive Threshold and the Release of Substance P from the Rat Isolated Spinal Cord

“…The initial mechanical hyperalgesia after N T-3 injection may be attributable to activation of the autonomic system through an action on trkA receptors by a transient high concentration. NT-3 has been recently shown to mediate sympathetic neuron survival through a regulation of trkA receptors (Belliveau et al, 1997). NT-3-induced changes in mechanical threshold are in line with recent work suggesting that tactile sensation is a target for NT-3 (Airaksinen et al, 1996).…”

NGF activates the phosphorylation of MAP1B by GSK3β through the TrkA receptor and not the p75NTRreceptor

“…NGF increases axon outgrowth and stimulates MAP1B phosphorylation in rat superior cervical ganglion neurons To determine whether an NGF-dependent activation of GSK3b phosphorylation of MAP1B occurs in neurons, as it does in PC12 cells, we examined cultures of dissociated postnatal rat superior cervical ganglion neurons, which express TrkA and p75 NTR receptors (Belliveau et al 1997). In the absence of NGF, superior cervical ganglion neurons extend neurites in culture on a laminin and poly-D-lysine substrate (Figs 2a and b), but the length of these neurites, and the proportion of cells extending a neurite, is markedly increased by addition of NGF (Figs 2a and b).…”

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

“…NT-3 and NGF signaling via TrkA control sympathetic neuronal development and differentially regulate survival and differentiation (6,7). Therefore, we aimed to determine TrkA subdomains involved in NGF and NT-3 binding and the functional outcome of NGF and NT-3 binding to their "hot spots" epitopes on TrkA receptors.…”

“…Furthermore, sympathetic neurons from NGF null and NT-3 null mice die when these neurons express high levels of TrkA and negligible levels of TrkC (5). NT-3 mediates neuritogenesis as effectively as NGF, but it affords ϳ20 -40-fold less survival compared with NGF in NGF-dependent sympathetic neurons (6). Also, NGF and NT-3 acting via TrkA are required for sympathetic axon growth and target innervation (7).…”