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

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Abstract
The patterns of nociceptive innervation in skin and spinal cord differ in mammals and lower vertebrates. Guo et al. report that nerve growth factor induces the transcription factor Hoxd1 in mouse, but not chick, sensory neurons, and that expression of Hoxd1 is necessary and sufficient for a mammalian-like pattern of nociceptive projections in vivo. Species are endowed with unique sensory capabilities that are 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 nerve growth factor (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. NGF promoted robust expression of Hoxd1 in mice, but not chickens, both in vivo and in vitro. Mice lacking Hoxd1 displayed altered nociceptor circuitry that resembles that normally found in chicks. Conversely, ectopic expression of Hoxd1 in developing chick nociceptors promoted a pattern of axonal projections reminiscent of the mouse. Thus, conserved growth factors control divergent neuronal transcriptional events that mediate interspecies differences in neural circuits and the behaviors that they control.

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