Genetic Control of the Segregation of Pain-Related Sensory Neurons Innervating the Cutaneous versus Deep Tissues

• Runx1-dependent DRG neurons innervate superficial ectodermal tissues
• Runx1-suppressed genes mark DRG neurons innervating mesodermal and endodermal tissues
• Cutaneous and deep pain is differentially impaired in complementary Runx1 mutants
• A genetic program for segregation of topographically distinct DRG neurons

SummaryMammalian pain-related sensory neurons are derived from TrkA lineage neurons located in the dorsal root ganglion. These neurons project to peripheral targets throughout the body, which can be divided into superficial and deep tissues. Here, we find that the transcription factor Runx1 is required for the development of many epidermis-projecting TrkA lineage neurons. Accordingly, knockout of Runx1 leads to the selective loss of sensory innervation to the epidermis, whereas deep tissue innervation and two types of deep tissue pain are unaffected. Within these cutaneous neurons, Runx1 suppresses a large molecular program normally associated with sensory neurons that innervate deep tissues, such as muscle and visceral organs. Ectopic expression of Runx1 in these deep sensory neurons causes a loss of this molecular program and marked deficits in deep tissue pain. Thus, this study provides insight into a genetic program controlling the segregation of cutaneous versus deep tissue pain pathways.

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