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Cell Rep. 2019 Mar 26;26(13):3522-3536.e5. doi: 10.1016/j.celrep.2019.02.097.

Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA.

Author information

1
ULB Neuroscience Institute (UNI), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium.
2
ULB Neuroscience Institute (UNI), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium; KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, 3000 Leuven, Belgium.
3
Institute of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University of Goettingen, 37077 Goettingen, Germany.
4
Cambridge Institute for Medical Research, University of Cambridge, CB2 0QQ Cambridge, UK.
5
KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, 3000 Leuven, Belgium.
6
Cambridge Institute for Medical Research, University of Cambridge, CB2 0QQ Cambridge, UK; Department of Medical Genetics, University of Cambridge, CB2 0XY Cambridge, UK.
7
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), 1030 Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria.
8
ULB Neuroscience Institute (UNI), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium. Electronic address: ebellefr@ulb.ac.be.

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.

KEYWORDS:

Xenopus; cell fate specification; mouse; neurotrophic receptor; nociceptors; pain; stem cells; zinc-finger transcription factor

PMID:
30917309
DOI:
10.1016/j.celrep.2019.02.097
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