Stat3 has a different role in axon growth during development than it does in axon regeneration after injury

Signal transducer and activator of transcription 3 (STAT3) is essential for neural development and regeneration as a key transcription factor and mitochondrial activator. In this study, using zebrafish posterior lateral line (PLL) axons, we demonstrate that Stat3 plays distinct roles in PLL axon embryonic growth and regeneration. In zebrafish stat3 mutants the PLL axons were truncated during embryonic growth. Expressing stat3 in neurons of the PLL ganglion rescued their axon growth suggesting stat3 promoted PLL axon growth in a cell-autonomous manner. Using Jak/Stat signaling inhibitors or modified Stat3, we found Jak/Stat signaling was dispensable for PLL axon growth. We showed that Stat3 was co-localized with mitochondria in PLL axon and lower ATPase activity in stat3 mutant embryos than wild-type embryos. The PLL axon growth was affected by mitochondrial modulators indicating that Stat3 regulated PLL axon growth through mitochondrial Stat3 function. Mutation of stat3 or treating with Jak/Stat signaling inhibitors retarded PLL axon regeneration and Schwann cell migration. Taken together, Stat3 is required for embryonic PLL axon growth by regulating the ATP synthesis efficiency of mitochondria, whereas Stat3 stimulates PLL axon regeneration through regulating Schwann cell migration via Jak/Stat signaling. Our findings show a new mechanism of Stat3 in axon growth and regeneration. Author Summary Neurons are one of the most specialized cell type in our body. A slender axon used for transmitting information between neuron and target cell extends from the cell body. Axon extension during both development and regeneration is regulated by intrinsic and extrinsic factors. In this study, we used the zebrafish posterior lateral line (PLL) axons which extends a long distance to study the regulation of axon extension. Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor in Jak/Stat signaling and an activator for mitochondria functions. Our results demonstrate that Stat3 plays distinct roles in PLL axons development and regeneration. During embryonic development, Jak/Stat signaling is dispensable for PLL axons extension, whereas the mitochondrial Stat3 is required for embryonic axon growth through promoting ATP synthesis. During PLL axons regeneration, Jak/Stat is essential for Schwann cells migration which mediates axon regeneration. ### Competing Interest Statement The authors have declared no competing interest.