Uncoupling of molecular maturation from peripheral target innervation in nociceptors expressing a chimeric TrkA/TrkC receptor

PLoS Genet. 2014 Feb 6;10(2):e1004081. doi: 10.1371/journal.pgen.1004081. eCollection 2014 Feb.

Abstract

Neurotrophins and their receptors control a number of cellular processes, such as survival, gene expression and axonal growth, by activating multiple signalling pathways in peripheral neurons. Whether each of these pathways controls a distinct developmental process remains unknown. Here we describe a novel knock-in mouse model expressing a chimeric TrkA/TrkC (TrkAC) receptor from TrkA locus. In these mice, prospective nociceptors survived, segregated into appropriate peptidergic and nonpeptidergic subsets, projected normally to distinct laminae of the dorsal spinal cord, but displayed aberrant peripheral target innervation. This study provides the first in vivo evidence that intracellular parts of different Trk receptors are interchangeable to promote survival and maturation of nociceptors and shows that these developmental processes can be uncoupled from peripheral target innervation. Moreover, adult homozygous TrkAC knock-in mice displayed severe deficits in acute and tissue injury-induced pain, representing the first viable adult Trk mouse mutant with a pain phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental
  • Gene Knock-In Techniques
  • Mice
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Neurons, Afferent / metabolism
  • Nociceptors
  • Pain / genetics*
  • Pain / pathology
  • Receptor, trkA / genetics*
  • Receptor, trkC / genetics*
  • Signal Transduction / genetics
  • Spinal Cord / growth & development*
  • Spinal Cord / metabolism

Substances

  • Nerve Growth Factors
  • Receptor, trkA
  • Receptor, trkC

Grants and funding

This work has been funded by ANR-Nociceptor diversity and FRM #SPF20081215079. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.