Prdm12 modulates pain-related behavior by remodeling gene expression in mature nociceptors

Abstract

Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors. Prdm12 expression is maintained in mature nociceptors suggesting a yet-to-be explored functional role in adults. Using Prdm12 inducible conditional knockout mouse models, we report that in adult nociceptors Prdm12 is no longer required for cell survival but continues to play a role in the transcriptional control of a network of genes, many of them encoding ion channels and receptors. We found that disruption of Prdm12 alters the excitability of dorsal root ganglion neurons in culture. Phenotypically, we observed that mice lacking Prdm12 exhibit normal responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. Together, our data indicate that Prdm12 regulates pain-related behavior in a complex way by modulating gene expression in adult nociceptors and controlling their excitability. The results encourage further studies to assess the potential of Prdm12 as a target for analgesic development.

The temporal refinement ofDach1is a key step in the functional maturation of primary somatosensory neurons

“…In early born nociceptors, Prdm12 represses the out-of-context expression of visceral determinants Phox2a/b and is required for nociceptor development and survival through the initiation and maintenance of the expression of Ntrk1/TrkA. In adult nociceptors, it modulates genes in a way that affects nociceptors homeostasis 20,22,23,25,55 . Through depletion of Prdm12 in late post-mitotic nociceptors using Scn10a Cre/+ ; Prdm12 flox/flox mice, we were able to deplete Prdm12 in a model that did not result in Phox2a/b ectopic expression or in agenesis of the nociceptive lineage 25 .…”

Loss of G9a does not phenocopy the requirement for Prdm12 in the development of the nociceptive neuron lineage

“…Accordingly, in human, patients harbouring homozygous mutations of PRDM12 suffer from congenital insensitivity to pain (CIP), a rare developmental disorder associated with depletion of somatosensory fibers allowing the detection of noxious stimuli [ 15 , 16 ]. Moreover, as Prdm12 remains expressed in mature nociceptive neurons and its induced conditional ablation at adulthood alters some pain-related behaviours, it has been hypothesized as a potential new therapeutic target to treat pain related diseases [ 16 , 17 ]. However, to approach the therapeutic potential of Prdm12, a deeper understanding of its mode of action needs to be first established.…”

Loss of G9a does not phenocopy the requirement for Prdm12 in the development of the nociceptive neuron lineage

“…Accordingly, in human, patients harbouring homozygous mutations of PRDM12 suffer from congenital insensitivity to pain (CIP), a rare developmental disorder associated with depletion of somatosensory fibers allowing the detection of noxious stimuli [14,15]. Moreover, as Prdm12 remains expressed in mature nociceptive neurons and its induced conditional ablation at adulthood alters some pain-related behaviours, it has been hypothesized as a potential new therapeutic target to treat pain related diseases [10,16,17]. However, to approach the therapeutic potential of Prdm12, a deeper understanding of its mode of action needs to be first established.…”