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Cell Rep January 1, 2019; 26 (13): 3522-3536.e5.

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

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 , Bellefroid EJ .

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.

PubMed ID: 30917309
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: astl2c en1 foxi4.1 neurog1 neurog2 ngf ntrk1 ntrk2 ntrk3 pax3 prdm12 six1 trpv1 tubb2b zic1
GO keywords: neurotrophin receptor activity [+]

Disease Ontology terms: pain agnosia

Article Images: [+] show captions