Tlx3 and Runx1 Act in Combination to Coordinate the Development of a Cohort of Nociceptors, Thermoceptors, and Pruriceptors

Neurons in the mouse dorsal root ganglia (DRGs) are composed of a variety of sensory modalities, such as pain-related nociceptors, itch-related pruriceptors, and thermoceptors. All these neurons are derived from late-born neurons that are initially marked by the expression of the nerve growth factor receptor TrkA. During perinatal and postnatal development, these TrkA lineage neurons are globally segregated into Ret-expressing and TrkA-expressing subtypes, and start to express a variety of sensory receptors and ion channels. The runt domain transcription factor Runx1 plays a pivotal role in controlling these developmental processes, but it remains unclear how it works. Here we showed that the homeodomain transcription factor Tlx3, expressed broadly in DRG neurons, is required to establish most Runx1-dependent phenotypes, including the segregation of TrkA-expressing versus Ret-expressing neurons and the expression of a dozen of sensory channels and receptors implicated in sensing pain, itch and temperature. Expression of Runx1 and Tlx3 is independent of each other at prenatal stages when they first establish the expression of these channels and receptors. Moreover, overexpression of Runx1 plus Tlx3 was able to induce ectopic expression of sensory channels and receptors. Collectively, these studies suggest that genetically Tlx3 acts in combination with Runx1 to control the development of a cohort of nociceptors, thermoceptors, and pruriceptors in mice.