Mesenchyme homeobox protein 2 (MEOX2) is a transcriptional factor involved in mesoderm differentiation, including development of bones and muscles, vasculature and dermatomes. Previously we have identified dysregulation of MEOX2 in fibroblasts from Congenital Insensitivity to Pain (CIP) patients, and confirmed that btn, Drosophila homologue of MEOX2, plays a role in nocifensive responses to noxious heat stimuli. To determine whether MEOX2 also plays a role in the mammalian nervous system we used MEOX2 haploinsufficient mouse model to characterize its function in sensory nervous system, specifically, nociception. Here, we report that MEOX2 is expressed in the mouse dorsal root ganglia (DRG) and spinal cord, and localizes in the nuclei of a subset of sensory neurons. Functional studies, including electrophysiological analysis and acute and inflammatory pain behavioral assays, show impaired nociception, encompassing impaired action potential firing upon depolarization as well as impaired behavioral responses to noxious heat and intraplantar capsaicin injections. We also find decreased expression of Scn9a and Scn11a, genes encoding Nav1.7 and Nav1.9 voltage gated sodium channels, respectively, specific for nociceptors crucial in subthreshold amplification and action potential initiation. These findings are supported by transcriptomic analyses of Meox2+/- DRGs which reveal downregulation of a specific subset of genes associated with pain perception, including PENK and NPY. Based on these observations, we report a novel role of MEOX2 in peripheral sensory neurons critical for maintenance of a transcriptional program required for proper detection of acute and inflammatory noxious stimuli. Moreover, MEOX2 regulates nociception on the level of action potential initiation in nociceptors, by modulating expression levels of nociceptor specific sodium channels.

DISCOVERY OF NOVEL AND CONSERVED NOCICEPTIVE PATHWAYS IN CONGENITAL INSENSITIVITY TO PAIN