Acetylated microtubules are essential for touch sensation in mice
Morley, Shane J.
University College Cork
The sense of touch depends upon the transformation of mechanical energy into electrical signals by peripheral sensory neurons and associated cells in the skin. This conversion is thought to be mediated by a complex of proteins in which ion channels such as Piezo2 function as mechanotransducers. However, how mechanical energy is transmitted into mechanosensitive ion channel opening, and how cellular components such as the cytoskeleton influence this process, is largely unknown. Here we show that mice lacking the tubulin acetyltransferase, Atat1, in sensory neurons display profound deficits in their ability to detect mechanical touch and pain. In the absence of Atat1, behavioural responses to innocuous and noxious mechanical stimuli are strongly reduced in multiple assays while sensitivity of mice to thermal stimuli is unaltered. In ex vivo skin-nerve preparations, the mechanosensitivity of all low- and high- threshold mechanoreceptor subtypes innervating the skin is substantially decreased in Atat1 conditional knockout mice. In cultured dorsal root ganglion neurons, both slowly- and rapidly- adapting mechanically- activated currents are absent or reduced upon Atat1 deletion with no effect on other neuronal functions. We establish that this broad loss of mechanosensitivity is dependent upon the acetyltransferase activity of Atat1, and that by mimicking α-tubulin acetylation genetically by substituting the lysine amino acid for a structurally similar glutamine, mechanosensitivity can be restored in Atat1- deficient sensory neurons. Finally, we demonstrate that acetylated microtubules localize to a prominent band under the membrane of sensory neuron cell bodies and axons, and in the absence of Atat1 and acetylated α-tubulin, cultured sensory neurons display significant reductions in their membrane elasticity. Our results indicate that the microtubule cytoskeleton is an essential component of the mammalian mechanotransduction complex and that by influencing cellular stiffness, α-tubulin acetylation can tune mechanical sensitivity across the full range of mechanoreceptor subtypes.
Neuroscience , Mechanosensation , Microtubules
Morley, S. J. 2016. Acetylated microtubules are essential for touch sensation in mice. PhD Thesis, University College Cork.