Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway.

Micro-RNAs (miRNAs) play roles in the mammalian central nervous system (CNS) development and disease but the functions of specific miRNA families' members in defined neuronal types are poorly understood. Here, we characterized the miR-135 family members in the mouse CNS retinal ganglion cell (RGC) and cortical projection neurons development, and tested whether reverting expression toward embryonic levels for the identified developmentally regulated miR-135 family members may reactivate the intrinsic axon growth capacity following axonal injury in the adult CNS. We found that two-out-of-five miR-135 family members, miR-135a-1-3p and miR-135b-3p, were developmentally downregulated, with further downregulation after axonal injury, in neurons. Importantly, RGC-targeted mimics of miR-135a-1-3p and miR-135b-3p promoted neuroprotection and axon regeneration following optic nerve injury, with axons regrowing through a segment of the central visual pathway when co-treated with an axon growth-supporting small fibronectin-based recombinant protein. Finally, transcriptomic profiling of the treated RGCs showed that genes involved in neurodevelopment/neuroprotection were embedded in the gene networks affected by the treatments. Thus, miR-135a-1-3p and miR-135b-3p are developmentally downregulated in the mammalian CNS projection neurons and present options for translation toward CNS injury treatments.