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. 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. [Display omitted] •A Hox code defines MNs projecting along the major axes of the limb•Ret and Gfrα genes are key targets of Hox proteins in limb-innervating MNs•Hox/Hox cofactor interactions govern Ret levels and Gfrα patterns in MNs•Loss of Ret and Gfrα3 causes MN defects similar to Hox gene mutations Catela et al. show that a network of Hox transcription factors governs the differentiation and connectivity of motor neurons through orchestrating the expression of Ret and Gfrα receptors. These findings indicate that Hox proteins facilitate synaptic specificity through controlling both the level and pattern of cell surface receptor expression.