PRDM12 Is Transcriptionally Active and Required for Nociceptor Function Throughout Life

Kokotović, Tomislav; Langeslag, Michiel; Lenartowicz, Ewelina M.; Manion, John; Fell, Christopher W.; Alehabib, Elham; Tafakhori, Abbas; Darvish, Hossein; Bellefroid, Éric; Neely, G. Gregory; Kress, Michaela; Penninger, Josef; Nagy, Vanja

doi:10.3389/fnmol.2021.720973

Cited by 8 publications

(15 citation statements)

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“…We originally observed a significant change in expression of MEOX2 mRNA in fibroblasts harvested from CIP patients with mutations in a methyl transferase, PRDM12 [8]. While we found co‐labelling of PRDM12 and MEOX2 in a small number of cells in the adult mouse DRG (not shown), we did not detect dysregulated Meox2 mRNA levels in classical PRDM12 knock‐out mice [63] nor in specific PRDM12 DRG‐specific knock outs ( Prdm12fl/fl; Avil‐Cre + ) by RNAseq [64]. Likewise, we were also unable to detect any changes in MEOX2 protein levels in Prdm12fl/fl; Avil‐Cre + DRG by Western blotting (data not shown).…”

Section: Discussionmentioning

confidence: 93%

Transcription factor mesenchyme homeobox protein 2 (MEOX2) modulates nociceptor function

et al. 2022

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Mesenchyme homeobox protein 2 (MEOX2) is a transcription factor involved in mesoderm differentiation, including development of bones, muscles, vasculature and dermatomes. We have previously identified dysregulation of MEOX2 in fibroblasts from Congenital Insensitivity to Pain patients, and confirmed that btn, the Drosophila homologue of MEOX2, plays a role in nocifensive responses to noxious heat stimuli. To determine the importance of MEOX2 in the mammalian peripheral nervous system, we used a Meox2 heterozygous (Meox2 +/À ) mouse model to characterise its function in the sensory nervous system, and more specifically, in nociception. MEOX2 is expressed in the mouse dorsal root ganglia (DRG) and spinal cord, and localises in the nuclei of a subset of sensory neurons. Functional studies of the mouse model, including behavioural, cellular and electrophysiological analyses, showed altered nociception encompassing impaired action potential initiation upon depolarisation. Mechanistically, we noted decreased expression of Scn9a and Scn11a genes encoding Na v 1.7 Abbreviations Actn3, gene, Actinin alpha 3; Ampd1-gene, adenosine monophosphate deaminase 1; AP, action potential; Bcl9l-gene, b-catenin transcriptional co-activator with BCL9,; Btn, gene, Buttonless; CACNA1S-gene, calcium voltage channel subunit alpha 1S; Calca-gene, calcitonin-related polypeptide alpha; CGRP, calcitonin gene-related peptide; CIP, congenital insensitivity to pain; DAPI, 4 0 ,

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Section: Discussionmentioning

confidence: 93%

Transcription factor mesenchyme homeobox protein 2 (MEOX2) modulates nociceptor function

et al. 2022

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“…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.…”

Section: Resultsmentioning

confidence: 99%

A compendium of validated pain genes

Wistrom

Chase

Smith

et al. 2022

WIREs Mechanisms of Disease

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The development of novel pain therapeutics hinges on the identification and rigorous validation of potential targets. Model organisms provide a means to test the involvement of specific genes and regulatory elements in pain. Here we provide a list of genes linked to pain‐associated behaviors. We capitalize on results spanning over three decades to identify a set of 242 genes. They support a remarkable diversity of functions spanning action potential propagation, immune response, GPCR signaling, enzymatic catalysis, nucleic acid regulation, and intercellular signaling. Making use of existing tissue and single‐cell high‐throughput RNA sequencing datasets, we examine their patterns of expression. For each gene class, we discuss archetypal members, with an emphasis on opportunities for additional experimentation. Finally, we discuss how powerful and increasingly ubiquitous forward genetic screening approaches could be used to improve our ability to identify pain genes. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Molecular and Cellular Physiology

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“…Although this article was under revision, Kokotovic and colleagues also reported that Prdm12 is required for nociceptor function in adult mice. 5,28 Further studies are obviously needed to better understand the complex mechanisms by which Prdm12 controls nociceptive neuron properties.…”

Section: Discussionmentioning

confidence: 99%

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

Latragna

José

Tsimpos

et al. 2021

Pain

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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.

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PRDM12 Is Transcriptionally Active and Required for Nociceptor Function Throughout Life

Cited by 8 publications

References 47 publications

Transcription factor mesenchyme homeobox protein 2 (MEOX2) modulates nociceptor function

Transcription factor mesenchyme homeobox protein 2 (MEOX2) modulates nociceptor function

A compendium of validated pain genes

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

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