A Neurotrophin Signaling Cascade Coordinates Sympathetic Neuron Development Through Differential Control of TrkA Trafficking and Retrograde Signaling

Cell. 2004 Jul 23;118(2):243-55. doi: 10.1016/j.cell.2004.06.021.


A fundamental question in developmental biology is how a limited number of growth factors and their cognate receptors coordinate the formation of tissues and organs endowed with enormous morphological complexity. We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 cannot. Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3. We propose that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TrkA internalization, trafficking, and retrograde axonal signaling.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axonal Transport / physiology
  • Cell Communication / physiology
  • Cell Differentiation / physiology
  • Endocytosis
  • Growth Cones / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Nerve Growth Factor / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Neurotrophin 3 / metabolism*
  • Protein Transport / physiology
  • Receptor, Nerve Growth Factor
  • Receptor, trkA / metabolism*
  • Receptors, Nerve Growth Factor / metabolism
  • Signal Transduction / physiology
  • Sympathetic Nervous System / cytology
  • Sympathetic Nervous System / growth & development*
  • Sympathetic Nervous System / metabolism*


  • Neurotrophin 3
  • Receptor, Nerve Growth Factor
  • Receptors, Nerve Growth Factor
  • Nerve Growth Factor
  • Receptor, trkA