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Abstract
Identifying 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, downregulation of LIFR strongly suppresses the pro-regenerative effects of Pten deletion and other potent stimuli. LIFR modulation alters the constitutive activity of the MAP kinase pathway, in contrast to LIF itself, which primarily activates pSTAT3. The extracellular-domain-truncated LIFR construct retains substantial pro-regenerative activity, whereas mutation of intracellular signaling motifs reduces the full regenerative effect of LIFR. Together, these findings identify LIFR as a key cell-autonomous regulator of optic nerve regeneration in mature RGCs.
Authors
Qian Jiang, Cong Wang, Yuerong Ren, Peiyun Duan, Ke Tian, Xiangwei Duan, Binghan Cai, Changzhong Xu, Ke Liu, Jian Li, Larry Benowitz, Ningli Wang, Bing Jiang, Lili Xie
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