Our ability to detect and respond to painful stimuli, including temperature, is achieved by nociceptors, a type of peripheral sensory neuron. During embryonic development, peptidergic nociceptors can be defined by their expression of TrkA, a receptor for nerve growth factor (NGF), and the transcription factor Etv4. Fernanda Ledda and colleagues previously demonstrated that Etv4 is upregulated by NGF and is required for axonal growth of peptidergic TrkA+ neurons in culture. In this issue, the authors expand on these findings and demonstrate that Etv4 ablation in mice results in a reduced response to NGF and thus attenuated development of peptidergic projections in vivo, without compromising neuronal viability. Consequently, Etv4-null mice display reduced response to noxious heat and chemical stimuli. Mechanistically, the authors find that Etv4-null mice have significantly reduced expression of the pain-transducing ion channel TRPV1. Additionally, expression of extracellular matrix (ECM) metalloproteinases in response to NGF is significantly reduced by loss of Etv4. Together, these findings suggest that Etv4 is required for NGF-induced expression of TRPV1 and ECM components necessary for correct development of peptidergic nociceptors. Thus, this study sheds light on the mechanistic underpinnings and importance of Etv4 in peripheral nociception.
