METTL5-mediated 18S rRNA m6A modification promotes corticospinal tract sprouting after unilateral traumatic brain injury

Abstract

The key to improving function of an impaired limb after unilateral brain injury is promotion of corticospinal tract (CST) sprouting across the midline into the denervated hemicord. Previous studies have unveiled specific genes that regulate CST sprouting. CST sprouting may also be regulated by RNA modification. We examined METTL5, the methyltransferase for 18S rRNA m⁶A modification, as a regulator of CST sprouting in mice. Overexpression of METTL5 in contralesional corticospinal neurons promoted CST sprouting after unilateral traumatic brain injury. Mechanically, METTL5-mediated 18S rRNA m⁶A modification promoted the translation efficiency (TE) of various genes. Notably, the upregulation of TE in the gene Cfl1, which encodes cofilin, led to an increase in its expression. Additionally, the upregulation of TE in the gene Inpp5k led to the activation of cofilin. Active cofilin stimulates actin polymerization and facilitates protrusion and bundling of microtubules, thus promoting axon outgrowth. These findings offer valuable insights for developing novel strategies to promote CST sprouting.