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Prdm12 directs nociceptive sensory neuron development by regulating the expression of the NGF receptor TrkA

par Desiderio, Simon ;Vermeiren, Simon ;Van Campenhout, Claude ;Kricha, Sadia ;Malki, Elisa;Fletcher, Emily E;Vanwelden, Thomas T;Schmidt, Bela;Henningfeld, Kristine A;Pieler, Thomas;Woods, C Geoffrey;Nagy, Vania;Verfaillie, Catherine;Bellefroid, Eric
Référence Cell reports, 26, 13, page (3522-3536)
Publication Publié, 2019-04

Article révisé par les pairs

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Résumé :

In human, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, required for survival and specification of nociceptors, and which plays a major role in pain processing. Mutations in PRDM12 have recently been identified in CIP patients indicating a putative role for this epigenetic modifier in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we found that Prdm12 is required for the initiation and maintenance of the expression of TrkA, by acting as a modulator of Neurogenin1/2 transcription factor activity, both in frogs, mice and humans. Together, our results identify Prdm12 as an evolutionarily conserved epigenetic regulator of nociceptor specification, and as an actionable target for new pain therapeutics.