A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons

Neuron. 2007 Jun 7;54(5):739-54. doi: 10.1016/j.neuron.2007.04.027.


NGF controls survival, differentiation, and target innervation of both peptidergic and nonpeptidergic DRG sensory neurons. The common receptor for GDNF family ligands, Ret, is highly expressed in nonpeptidergic neurons, but its function during development of these neurons is unclear. Here, we show that expression of Ret and its coreceptors GFRalpha1 and GFRalpha2 is dependent on NGF. GFR/Ret signaling, in turn, autoregulates expression of both GFRalpha1 and GFRalpha2 and promotes expression of TrpA1, MrgA1, MrgA3, and MrgB4, acquisition of normal neuronal size, axonal innervation of the epidermis, and postnatal extinction of the NGF receptor TrkA. Moreover, NGF controls expression of several other genes characteristic of nonpeptidergic neurons, such as TrpC3, TrpM8, MrgD, and the transcription factor Runx1, via a Ret-independent signaling pathway. These findings support a model in which NGF controls maturation of nonpeptidergic DRG neurons through a combination of GFR/Ret-dependent and -independent signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / embryology*
  • Ganglia, Spinal / metabolism
  • Gene Expression Regulation, Developmental / physiology
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Ion Channels / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Growth Factor / metabolism*
  • Neurons, Afferent / cytology
  • Neurons, Afferent / metabolism*
  • Nociceptors / cytology
  • Nociceptors / embryology*
  • Nociceptors / metabolism
  • Organ Culture Techniques
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / metabolism


  • Gfra1 protein, mouse
  • Gfra2 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Ion Channels
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Nerve Growth Factor
  • Proto-Oncogene Proteins c-ret