Therapeutic Intervention of Corticospinal Tract Sprouting after Unilateral Traumatic Brain Injury via METTL1-Mediated tRNA m7G Modification

Corticospinal tracts (CST) from the contralateral side spontaneously sprouting into the denervated motor neurons in the impaired spinal hemicord allow the contralateral motor cortex to control the paralyzed limb, improving the impaired limb function after unilateral brain injury. However, the intrinsic potential for axon outgrowth in adults is limited, restricting the functional recovery through CST sprouting. While ribosomal RNA modification has been reported in regulating CST sprouting, the role of transfer RNA (tRNA) modifications remains unclear. Here, we investigated METTL1, the methyltransferase for tRNA m7G modification, as a potential regulator of CST sprouting. In a mouse model of unilateral traumatic brain injury, we found overexpression of METTL1 in contralesional corticospinal neurons improved motor function recovery and promoted CST sprouting. Mechanistically, METTL1 upregulates tRNA m7G modification level, which augments the translation efficiency of mRNAs associated with axon outgrowth, particularly those within the mTOR signaling pathway. Critically, pharmacological inhibition of mTOR signaling with rapamycin diminishes the beneficial effects of METTL1 overexpression on axon outgrowth and CST sprouting. Our findings reveal a novel role for METTL1-mediated tRNA m7G modification in promoting neural repair and identify a potential therapeutic strategy for enhancing recovery after unilateral brain injury.