par Bellefroid, Eric
Référence Pain Mechanisms and Therapeutics Conference (3-8 june, 2018: Taormina, Sicicly)
Publication Non publié, 2018
Communication à un colloque
Résumé : In a recent study on individuals with Congenital Insensitivity to Pain (CIP), the Prdm12 gene has been identified as a novel gene causing painlessness that is required for the development of the nociceptors, the specialized neurons sensing tissue damage. Despite its importance in nociceptors, its exact function and mechanism of action remains elusive. Here we show that during mouse embryonic development, within the dorsal root ganglia that contains the cell bodies of the different types of sensory neurons, Prdm12 is selectively expressed in developing nociceptors and that in adults it remains expressed in mature nociceptors. Via the generation and characterization of null and conditional Prdm12 mutant lines, we demonstrate that Prdm12 is required in nociceptor progenitors for their survival, likely due to its requirement for the initiation of the expression of the neurotrophic receptor TrkA, and provide evidence that it is also essential in later maturing nociceptors for the expression of many pain-associated channels and receptors. Furthermore, using gain of function assays in pluripotent animal cap ectodermal explants, we show that Prdm12 promotes the ability of the proneural factor Neurogenin1 and 2 to induce TrkA expression and blocks their capacity to induce other sensory cell fates. Taken together, our findings point to Prdm12 as a critical regulator of nociceptor development and provide first explanation for its mechanism of action in sensory neurogenesis. Its role in mature nociceptive neurons and pain perception is currently studied assessing their electrophysiological properties and the behaviour responses of Prdm12 cKO mice to noxious stimuli.