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

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. Weshow that Hox/Hox cofactor interactions coordinate MN subtype diversification and connectivity through Ret/Gfr alpha receptor genes. Hox and Meis proteins determine the levels of Ret in MNs and define the intrasegmental profiles of Gfr alpha 1 and Gfr alpha 3 expression. Loss of Ret or Gfr alpha 3 leads to MN specification and innervation defects similar to those observed in Hox mutants, while expression of Ret and Gfr alpha 1 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.