Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Abstract

Prdm12 is as a key transcription factor in nociceptor neurogenesis. Mutations of Prdm12 cause Congenital Insensitivity to Pain (CIP) due to failure of nociceptor development. However, precisely how deletion of Prdm12 during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function of Prdm12 during development and in adulthood. We find that constitutive loss of Prdm12 causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that in adult DRGs, Prdm12 is dispensable for pain sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we found unique changes in adult Prdm12 knockout DRGs compared to embryonic knockout, and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.

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

“…Landy and colleagues recently published the results of bulk RNA-seq analysis of DRGs of adult Prdm12 knockout mice, generated as we have done by crossing Avil CreERT2 mice to Prdm12 fl/fl mice. 30 In contrast to our results, they found that almost all DEGs were decreased in mutant mice. Comparing their transcriptomic data to our list of DEGs identified in DRG, surprisingly, only 1 common gene was found, Chrna6 .…”

“…Despite the effects of Prdm12 deficiency on transcription, we found that mice lacking Prdm12 exhibit normal thermosensation and itch response. Unaltered response to noxious cold is somehow surprising given the fact that we found that Trpm8 expression is reduced in Prdm12 icKO mice, as observed by Landy et al (2021). This unaltered response to acute noxious cold may be because of the fact that Trpm8 expression is reduced but not abolished in DRG neurons of icKO mice.…”

“…To determine whether Prdm12 plays a role in the control of gene expression in mature nociceptors, we performed a transcriptomic analysis by bulk RNA-seq on dissected lumbar DRG of both Avil and Rosa26 icKO models and control mice 1 month after TAM injection. Using an FDR-adjusted P -value ≤0.05 and an absolute log2 fold-change cut-off of ≥0.449 (based on the fold-change of Ntrk1 , recently reported as reduced in adult Prdm12 knockout mice 30 ) we obtained a list of 140 candidate genes in Avil icKO mice and 134 in Rosa26 icKO mice that are dysregulated in the absence of Prdm12 (Fig. 3A and Sup.…”

“…8,19 In addition, our data suggest that CFA-induced peripheral inflammation decreases Prdm12 expression in mature nociceptors. Deregulated expression of Prdm12 has also been observed in response to nerve injury 30 and in itch-sensitive neurons in response to dermatitis. 63 Whether this deregulation of Prdm12 expression plays a causative role in the transcriptional changes that occurs in these conditions remains unknown.…”

A compendium of validated pain genes

“…PRDM12 function was subsequently assayed in mammalian model systems. While germline deletion of PRDM12 and conditional knockout of PRDM12 in the embryonic neural crest was neonatal lethal, conditional knockout of PRDM12 in embryonic DRGs produced viable offspring (Kokotović et al, 2021; Landy et al, 2021). These mice displayed increased mortality and exhibited corneal abrasions and facial scarring similar to what is seen in human CIP patients; they also displayed decreased baseline sensitivity to mechanical and cold stimulation, decreased chemical sensitivity to capsaicin injection, and decreased itch response to chloroquine and histamine.…”