Figure 3.

Retinal ganglion cell (RGC) regeneration pathways. Successful axonal regeneration involves both RGC-intrinsic pathways and factors derived from surrounding cell types. Within RGCs, activation of the mTOR and STAT3 pathways both stimulate axonal regrowth. The mTOR pathway is inhibited by AKT, TSC1, and PTEN, and removal of any of those three genes stimulates pathway activation and regeneration. The STAT3 signaling pathway is partly activated by external factors, including the neurotrophins CNTF, LIF, and IGF-1, all secreted from cells near the RGCs (Müller glia, microglia, and monocyte-derived macrophages). Either application of these neurotrophins, removal of SOCS3 (a Stat3 inhibitor), or other methods of activating the Stat3 signaling pathway induces regeneration. Activated Stat3 localizes to both nucleus and mitochondria and is known to stimulate downstream gene expression changes in the nucleus. Also intrinsic to RGCs, a de-differentiation event occurs involving downregulation of differentiation genes (DGs) and upregulation of regeneration-associated genes (RAGs), involving diverse transcription factors which reprogram RGCs to a growth-capable state.