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

ABSTRACT: 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^+/- ) 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 and Na_v 1.9 voltage-gated sodium channels respectively, that are crucial in subthreshold amplification and action potential initiation in nociceptors. Further transcriptomic analyses of Meox2^+/- DRG revealed downregulation of a specific subset of genes including those previously associated with pain perception, such as PENK and NPY. Based on these observations, we propose a novel role of MEOX2 in primary afferent nociceptor neurons for the maintenance of a transcriptional programme required for proper perception of acute and inflammatory noxious stimuli.

SUBMITTER: Kokotovic T

PROVIDER: S-EPMC9306780 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPlants have the lifelong ability to generate new organs due to the persistent functioning of stem cells. In seed plants, groups of stem cells are housed in the shoot apical meristem (SAM), root apical meristem (RAM), and vascular cambium (VC). In ferns, a single shoot stem cell, the apical cell, is located in the SAM, whereas each root initiates from a single shoot-derived root initial. WUSCHEL-RELATED HOMEOBOX (WOX) family transcription factors play important roles to maintain stem-cell identity. WOX genes are grouped phylogenetically into three clades. The T3WOX/modern clade has expanded greatly in angiosperms, with members functioning in multiple meristems and complex developmental programs. The model fern Ceratopteris richardii has only one well-supported T3WOX/modern WOX gene, CrWUL. Its orthologs in Arabidopsis, AtWUS, AtWOX5, and AtWOX4, function in the SAM, RAM, and VC, respectively. Identifying the function of CrWUL will provide insights on the progenitor function and the diversification of the modern WOX genes in seed plants.ResultsTo investigate the role of CrWUL in the fern, we examined the expression and function of CrWUL and found it expresses during early root development and in vasculature but not in the SAM. Knockdown of CrWUL by RNAi produced plants with fewer roots and fewer phloem cells. When expressed in Arabidopsis cambium, CrWUL was able to complement AtWOX4 function in an atwox4 mutant, suggesting that the WOX function in VC is conserved between ferns and angiosperms. Additionally, the proposed progenitor of T3WOX genes from Selaginella kraussiana is expressed in the vasculature but not in the shoot apical meristem. In contrast to the sporophyte, the expression of CrWUL in the gametophyte exhibits a more general expression pattern and when knocked down, offered little discernable phenotypes.ConclusionsThe results presented here support the occurrence of co-option of the T3WOX/modern clade gene from the gametophyte to function in vasculature and root development in the sporophyte. The function in vasculature is likely to have existed in the progenitor of lycophyte T3WOX/modern clade genes and this function predates its SAM function found in many seed plants.

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

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