The sensory neurons in peripheral sensory ganglia, derived from neural crest precursors, are a highly diverse group of cells. A paper in this issue examines how the emergence of this diversity in the developing neurons is orchestrated. Subgroups of sensory neurons specialize in distinct sensory modalities, such as proprioception, nociception, heat, cold or touch. They differ in size, their projection areas, their degree of myelination, and their expression of receptors, channels and neuropeptides. The bHLH transcription factor Ngn2 is known to specify neural crest-derived sensory neurons in general, and a Runt family transcription factor, Runx3, defines the proprioceptive subpopulation. It thus seemed plausible that other Runt family members might be responsible for the differentiation of other sensory neuron subtypes.

Marmigère et al. (page 180) took a close look at Runx1. In chick embryo, Runx1 mRNA (blue pseudocolor in the figure) was found in neurons that were positive for TrkA (red immunolabel) but excluded from TrkA-negative cells. (All neurons in the image are co-immunolabeled with the marker Isl1 in green.) The co-localization of Runx1 with TrkA suggests a role for Runx1 in the specification of nociceptor neurons. Developing nociceptors depend on nerve growth factor (NGF) signaling through the TrkA receptor for survival. In a series of experiments overexpressing Runx1 and/or Ngn2 in earlier-stage progenitors, the authors determined that Runx1 acts together with Ngn2 to enable survival and axon growth of young neurons. Runx1 alone supported neither survival nor axon elongation. Suppression of all Runx family transcriptional regulation in ovo with a dominant-negative construct resulted in loss of the nociceptor marker TrkA and death of nearly all transfected neurons, whereas specific knockdown of Runx1 by RNA interference selectively killed the nociceptor subpopulation. The TrkA promoter region contains a putative Runx binding site, so authors presume that Runx1, in collaboration with other transcriptional regulators, directly activates TrkA transcription. Runx1 overexpression in progenitors induced precocious expression of TrkA.

Taken together, these results establish Runx1 as a master switch in the development of the neurons that transduce pain signals. Further work will unravel the web downstream of Runx1 and Ngn2, leading to a thorough understanding of nociceptors and hopefully some ideas about how to interfere with pathological pain states.