Nervous system development is orchestrated by transcription factors acting in sequence and in networks. The effectors that actually execute the steps leading to early specification or later phenotypic maturation of developing neurons are largely unknown. On pp. 1283–1293, Sun et al. identify some of these effectors, using the transcription factor Islet1 and its role in sensory neuron development as their model system.

The authors genetically excised Islet1 from the early mouse neural crest and dorsal neural tube. Dorsal root and trigeminal ganglia formed normally, but, from E12.5 onwards, most pain- and touch-sensitive neurons, as identified by TrkA, TrkB or Runx1 expression, died. Proprioceptive neurons were far less affected. The figure shows surviving proprioceptors, identified by Runx3 (red) and TrkC (green), in an E14.5 dorsal root ganglion (DRG) lacking Islet1.

How could the absence of Islet1 cause such specific apoptosis? The time course of Islet1 expression offered a partial explanation. Nearly all wild-type sensory neurons expressed Islet1 from approximately E10 onwards, but the proprioceptive cells had downregulated it by E14.5. Thus, they may not require Islet1-dependent pathways for differentiation and survival.

By immunostaining and gene expression analysis, Sun et al. reveal a complicated picture of how Islet1 functions in sensory neuron subtype differentiation. In the nociceptive lineage, initial induction of the receptor TrkA was independent of Islet1, whereas expression of the transcription factor Runx1 required it. The mRNA levels of several nociceptor-specific genes were substantially reduced in E12.5 DRG that lacked Islet1, among them the channels Nav1.8 and TRPV1. In the proprioceptive lineage, onset of TrkC expression was delayed, but expression of Runx3 was unaffected. Several mRNAs coding for transcription factors involved in earliest neuron specification or in hindbrain and spinal cord development were abnormally expressed in Islet1-null DRG. Thus, a major function of Islet1 seems to be the repression of inappropriate genetic programs.

One important question remains unanswered: how does Islet1 enable the survival of certain sensory neurons past E12.5? Future work, undoubtedly, will tell.