Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, CHANNEL EXPRESSION, GENE-EXPRESSION, ION-CHANNEL, TRP CHANNEL, STEM-CELLS, SPECIFICATION, NEUROGENESIS, GANGLION, FAMILY, PAX3, Xenopus, cell fate specification, mouse, neurotrophic receptor, nociceptors, pain, stem cells, zinc-finger transcription factor, Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Carrier Proteins, Cell Line, Evolution, Molecular, Female, Ganglia, Sensory, Gene Knockout Techniques, Human Embryonic Stem Cells, Humans, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Crest, Neurogenesis, Nociceptors, Receptor, trkA, Tretinoin, Xenopus laevis, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, 31 Biological sciences

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.