1. Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA.
- Author
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Desiderio S, Vermeiren S, Van Campenhout C, Kricha S, Malki E, Richts S, Fletcher EV, Vanwelden T, Schmidt BZ, Henningfeld KA, Pieler T, Woods CG, Nagy V, Verfaillie C, and Bellefroid EJ
- Subjects
- Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors metabolism, Carrier Proteins genetics, Cell Line, Evolution, Molecular, Female, Ganglia, Sensory cytology, Gene Knockout Techniques, Human Embryonic Stem Cells, Humans, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Crest cytology, Nociceptors metabolism, Receptor, trkA metabolism, Tretinoin physiology, Xenopus laevis, Carrier Proteins physiology, Nerve Tissue Proteins physiology, Neurogenesis physiology, Nociceptors cytology
- Abstract
In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. Mutations in PRDM12 have been identified in CIP patients that indicate a putative role for this transcriptional regulator 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 find 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, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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