An evolving NGF–Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates

Species are endowed with unique sensory capabilities encoded by divergent neural circuits. One potential explanation for how divergent circuits have evolved is that conserved extrinsic signals are differentially interpreted by developing neurons of different species to yield unique patterns of axonal connections. Although NGF controls survival, maturation and axonal projections of nociceptors of different vertebrates, whether the NGF signal is differentially transduced in different species to yield unique features of nociceptor circuits is unclear. We identified a species-specific signaling module induced by NGF and mediated by a rapidly evolving Hox transcription factor, Hoxd1. Mice lacking Hoxd1 display altered nociceptor circuitry which resembles that normally found in chicks. Conversely, ectopic expression of Hoxd1 in developing chick nociceptors promotes a pattern of axonal projections reminiscent of the mouse. We propose that conserved growth factors control divergent neuronal transcriptional events which mediate interspecies differences in neural circuits and the behaviors they control.