Optic nerve regeneration requires the intracellular domain of LIFRa/CD118

Identifying cell-autonomous and non-autonomous factors that govern retinal ganglion cells (RGCs) ability to extend axons is an important step in developing therapies to achieve recovery after optic nerve injury. Here we report that the intracellular domain of the leukemia inhibitory factor receptor (LIFR/CD118) is essential for mature RGCs ability to regenerate injured axons independent of the cognate ligand (LIF) and other therapies. Overexpression of LIFR in adult RGCs induces neurite outgrowth in cultured RGCs and axon regeneration in vivo while strongly amplifying RGCs response to LIF itself and to unrelated growth factors. Conversely, in loss-of-function studies, down-regulation of LIFR eliminates the pro-regenerative effects of Pten deletion and other potent stimuli. LIFR bidirectionally regulates the constitutive activity of the MAP kinase pathway, in contrast to LIF itself, which primarily activates pSTAT3. Expression of a truncated LIFR lacking the extracellular domain is sufficient to promote axon regeneration and selectively increases the survival of particular RGC subtypes, placing the LIFR intracellular domain as an essential, cell-autonomous regulator of optic nerve regeneration.