Raf Kinase Signaling Functions in Sensory Neuron Differentiation and Axon Growth in Vivo

Nat Neurosci. 2007 May;10(5):598-607. doi: 10.1038/nn1898. Epub 2007 Mar 29.

Abstract

To define the role of the Raf serine/threonine kinases in nervous system development, we conditionally targeted B-Raf and C-Raf, two of the three known mammalian Raf homologs, using a mouse line expressing Cre recombinase driven by a nestin promoter. Targeting of B-Raf, but not C-Raf, markedly attenuated baseline phosphorylation of Erk in neural tissues and led to growth retardation. Conditional elimination of B-Raf in dorsal root ganglion (DRG) neurons did not interfere with survival, but instead caused marked reduction in expression of the glial cell line-derived neurotrophic factor receptor Ret at postnatal stages, associated with a profound reduction in levels of transcription factor CBF-beta. Elimination of both alleles of Braf, which encodes B-Raf, and one allele of Raf1, which encodes C-Raf, affected DRG neuron maturation as well as proprioceptive axon projection toward the ventral horn in the spinal cord. Finally, conditional elimination of all Braf and Raf1 alleles strongly reduced neurotrophin-dependent axon growth in vitro as well as cutaneous axon terminal arborization in vivo. We conclude that Raf function is crucial for several aspects of DRG neuron development, including differentiation and axon growth.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Survival
  • Cells, Cultured
  • Embryo, Mammalian
  • Exons
  • Ganglia, Spinal / cytology
  • Gene Expression / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / physiology
  • Nerve Growth Factor / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons, Afferent / cytology*
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / physiology*
  • Rats
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Stem Cells / drug effects
  • Transfection
  • raf Kinases / genetics
  • raf Kinases / physiology*

Substances

  • Nerve Tissue Proteins
  • Nerve Growth Factor
  • raf Kinases