PT - JOURNAL ARTICLE AU - Aaron D. Johnstone AU - Andrés de Léon AU - Nicolás Unsain AU - Julien Gibon AU - Philip A. Barker TI - Developmental axon degeneration requires TRPV1-dependent Ca<sup>2+</sup> influx AID - 10.1523/ENEURO.0019-19.2019 DP - 2019 Feb 01 TA - eneuro PG - ENEURO.0019-19.2019 4099 - http://www.eneuro.org/content/early/2019/02/01/ENEURO.0019-19.2019.short 4100 - http://www.eneuro.org/content/early/2019/02/01/ENEURO.0019-19.2019.full AB - Development of the nervous system relies on a balance between axon and dendrite growth and subsequent pruning and degeneration. The developmental degeneration of dorsal root ganglion (DRG) sensory axons has been well studied in part because it can be readily modeled by removing the trophic support by nerve growth factor (NGF) in vitro. We have recently reported that axonal fragmentation induced by NGF withdrawal is dependent on Ca2+ and here we address the mechanism of Ca2+ entry required for developmental axon degeneration of mouse embryonic DRG neurons. Our results show that the Transient Receptor Potential Vanilloid family member 1 (TRPV1) cation channel plays a critical role mediating Ca2+ influx in DRG axons withdrawn from NGF. We further demonstrate that TRPV1 activation is dependent on reactive oxygen species (ROS) generation that is driven through protein kinase C (PKC) and NADPH oxidase (NOX) -dependent pathways that become active upon NGF withdrawal. These findings demonstrate novel mechanistic links between NGF deprivation, PKC activation, ROS generation and TRPV1-dependent Ca2+ influx in sensory axon degeneration.Significance Statement Neurons are equipped with the genetic means to degenerate, and a subset of peripheral neurons normally degenerate during embryonic development to establish a mature pattern. This beneficial neurodegeneration is regulated by signaling pathways that are only partially understood, yet share components with pathways that mediate pathological degeneration of crucial neural structures during adult diseases such as Alzheimer’s and Parkinson’s. Here, we identify TRPV1 as a key regulator of Ca2+ entry into axoplasm that is required for developmental degeneration modeled by NGF withdrawal from sensory neurons of the dorsal root ganglion in vitro. Crucially, we report that the TRPV1-mediated Ca2+ flux is prompted by a signaling axis comprised of PKC-dependent NOX complex activation and ROS generation upstream of TRPV1.