Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA.
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
Neural Crest
/ cytology
Neurogenesis
/ physiology
Nociceptors
/ cytology
Receptor, trkA
/ metabolism
Tretinoin
/ physiology
Xenopus laevis
Xenopus
cell fate specification
mouse
neurotrophic receptor
nociceptors
pain
stem cells
zinc-finger transcription factor
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 03 2019
26 03 2019
Historique:
received:
15
10
2018
revised:
21
01
2019
accepted:
25
02
2019
entrez:
28
3
2019
pubmed:
28
3
2019
medline:
21
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30917309
pii: S2211-1247(19)30283-9
doi: 10.1016/j.celrep.2019.02.097
pii:
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Carrier Proteins
0
Nerve Tissue Proteins
0
Neurog2 protein, mouse
0
Prdm12 protein, mouse
0
Neurog1 protein, mouse
182238-50-2
Tretinoin
5688UTC01R
Receptor, trkA
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3522-3536.e5Subventions
Organisme : Medical Research Council
ID : MR/R006237/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.