Knocking Out Non-muscle Myosin II in Retinal Ganglion Cells Promotes Long-Distance Optic Nerve Regeneration

In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here, we show that knocking out myosin IIA and IIB (myosin IIA/B) in retinal ganglion cells alone, either before or after optic nerve crush, induces significant optic nerve regeneration. Combined Lin28a overexpression and myosin IIA/B knockout lead to an additive promoting effect and long-distance axon regeneration. Immunostaining, RNA sequencing, and western blot analyses reveal that myosin II deletion does not affect known axon regeneration signaling pathways or the expression of regeneration-associated genes. Instead, it abolishes the retraction bulb formation and significantly enhances the axon extension efficiency. The study provides clear evidence that directly targeting neuronal cytoskeleton is sufficient to induce significant CNS axon regeneration and that combining altered gene expression in the soma and modified cytoskeletal dynamics in the axon is a promising approach for long-distance CNS axon regeneration. [Display omitted] •Myosin II KO in RGCs induces significant optic nerve regeneration•Myosin II KO does not affect gene transcription in RGCs•Myosin II KO reduces retraction bulbs and leads to efficient axon extension•Myosin II KO and Lin28a expression in RGCs produce long-distance axon regeneration Although modulating the neuronal cytoskeleton has been deemed a promising approach to enhance mammalian axon regeneration, only a few studies have shown convincing results, especially in the central nervous system. Wang et al. demonstrate that the deletion of non-muscle myosin II sufficiently induces significant mammalian CNS axon regeneration in vivo.