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Abstract

Mechanotransduction is the ability of living organisms to sense and respond to mechanical forces by converting them into a biological response. In mammals, mechanotransduction is mediated by specialized sensory neurons which are capable of detecting a wide range of mechanical stimuli, relying on the presence of mechanotransducer channels on sensory nerve endings. Surprisingly, little is known about the properties of mechanotransducers in mammals and thus the mechanisms that convert mechanical forces into electrical signals at the peripheral endings of sensory neurons and, especially how the cytoskeleton influences it. In previous work, we have found that mice lacking the -tubulin acetyltransferase Atat1 display a significant decrease in mechanosensitivity across all major fiber types innervating the skin, strongly affecting light touch and pain, with no impact on other sensory modalities1. We also assessed that such a phenotype does not arise from wide-ranging effects on the development, morphology and structure of peripheral sensory neurons but may be caused by the lack of a sub-membrane ring of acetylated -tubulin that somehow sets the mechanical rigidity of the cells, rendering them more resistant to mechanical deformation1. How -tubulin acetylation is capable of setting cellular rigidity remains poorly understood. Here, an ultrastructural analysis on sensory nerve endings was performed to examine whether the lack of -tubulin acetylation affect microtubules (MTs) organization and structure along the sensory neuron axis, from the soma of DRG neurons to their peripheral endings. Superresolution microscopy analysis on DRG neurons shows that the lack of -tubulin acetylation does not affect the overall MTs organization. Moreover, combining high-resolution transmission electron microscopy with image analysis, I investigated MT morphology and distribution in the saphenous nerve from Atat1control and Atat1cKO mice. Our results demonstrated that no major differences were observed between MTs from the Atat1cKO compared to the Atat1control when minor axis, eccentricity, solidity and perimeter length were compared. These results were also confirmed by Cryo-EM observations, suggesting that lack of acetylation does not affect MTs ultrastructure in mammals in the absence of mechanical stress. Finally, the von Frey assay shows that mice lacking Atat1 not only display a profound loss of light touch and pain sensitivity but, in addition, they develop allodynia only beginning at day 21 post SNI (spared nerve injury), suggesting that microtubule acetylation play an important role in hypersensitivity to mechanical stimuli associated with chronic pain.