Hox Proteins Coordinate Motor Neuron Differentiation and Connectivity Programs through Ret/Gfrα Genes

Cell Rep. 2016 Mar 1;14(8):1901-15. doi: 10.1016/j.celrep.2016.01.067. Epub 2016 Feb 18.

Abstract

The accuracy of neural circuit assembly relies on the precise spatial and temporal control of synaptic specificity determinants during development. Hox transcription factors govern key aspects of motor neuron (MN) differentiation; however, the terminal effectors of their actions are largely unknown. We show that Hox/Hox cofactor interactions coordinate MN subtype diversification and connectivity through Ret/Gfrα receptor genes. Hox and Meis proteins determine the levels of Ret in MNs and define the intrasegmental profiles of Gfrα1 and Gfrα3 expression. Loss of Ret or Gfrα3 leads to MN specification and innervation defects similar to those observed in Hox mutants, while expression of Ret and Gfrα1 can bypass the requirement for Hox genes during MN pool differentiation. These studies indicate that Hox proteins contribute to neuronal fate and muscle connectivity through controlling the levels and pattern of cell surface receptor expression, consequently gating the ability of MNs to respond to limb-derived instructive cues.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Chick Embryo
  • Embryo, Mammalian
  • Forelimb
  • Gene Expression Regulation, Developmental*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Mice
  • Motor Neurons / cytology
  • Motor Neurons / metabolism*
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / ultrastructure
  • Mutation
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neurogenesis / genetics
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism
  • Synapses / metabolism
  • Synapses / ultrastructure
  • Synaptic Transmission
  • Transcription Factors
  • Transcription, Genetic

Substances

  • Gfra1 protein, mouse
  • Gfra3 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Homeodomain Proteins
  • Hoxa5 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Phosphoproteins
  • Protein Isoforms
  • Transcription Factors
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse