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Stat3 Has a Different Role in Axon Growth During Development Than It Does in Axon Regeneration After Injury

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Abstract

Signal transducer and activator of transcription 3 (STAT3) is essential for neural development and regeneration as a key transcription factor and mitochondrial activator. However, the mechanism of Stat3 in axon development and regeneration has not been fully understood. In this study, using zebrafish posterior lateral line (PLL) axons, we demonstrate that Stat3 plays distinct roles in PLL axon embryonic growth and regeneration. Our experiments indicate that stat3 is required for PLL axon extension. In stat3 mutant zebrafish, the PLL axon ends were stalled at the level of the cloaca, and expression of stat3 rescues the PLL axon growth in a cell-autonomous manner. Jak/Stat signaling inhibition did not affect PLL axon growth indicating Jak/Stat was dispensable for PLL axon growth. In addition, we found that Stat3 was co-localized with mitochondria in PLL axons and important for the mitochondrial membrane potential and ATPase activity. The PLL axon growth defect of stat3 mutants was mimicked and rescued by rotenone and DCHC treatment, respectively, which suggests that Stat3 regulates PLL axon growth through mitochondrial Stat3. By contrast, mutation of stat3 or Jak/Stat signaling inhibition retarded PLL axon regeneration. Meanwhile, we also found Schwann cell migration was also inhibited in stat3 mutants. Taken together, Stat3 is required for embryonic PLL axon growth by regulating the ATP synthesis efficiency of mitochondria, whereas Stat3 stimulates PLL axon regeneration by regulating Schwann cell migration via Jak/Stat signaling. Our findings show a new mechanism of Stat3 in axon growth and regeneration.

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Acknowledgements

We thank Donghua Zhou, Yuanhang Chen, and Xujing Zhu, who participated in this study for their technical assistance and helpful discussions.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant 31772406 to C.F. and Grant 31702329 to J.W.).

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  1. Qinwen Duan and Hongfei Zheng contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China

    Qinwen Duan, Hongfei Zheng, Yanjun Qin, Jizhou Yan, Jian Wang & Chunxin Fan

  2. International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China

    Qinwen Duan, Hongfei Zheng, Yanjun Qin, Jizhou Yan, Jian Wang & Chunxin Fan

  3. Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    Shawn M. Burgess

  4. Marine Biomedical Science and Technology Innovation Platform of Lingang New Area, Shanghai, China

    Chunxin Fan

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Contributions

Qinwen Duan, Hongfei Zheng, and Chunxin Fan designed the study. Material preparation and data collection were performed by Qinwen Duan, Hongfei Zheng, and Yanjun Qin. Data analysis was performed by Qinwen Duan, Jian Wang, and Chunxin Fan. The first draft of the manuscript was written by Qinwen Duan and Chunxin Fan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chunxin Fan.

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The study was approved by the Animal Ethics Committee of Shanghai Ocean University (Approval Number: SHOU-DW-2021-051). All animal experiments were performed in accordance with a guide to animal ethics.

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Duan, Q., Zheng, H., Qin, Y. et al. Stat3 Has a Different Role in Axon Growth During Development Than It Does in Axon Regeneration After Injury. Mol Neurobiol 61, 1753–1768 (2024). https://doi.org/10.1007/s12035-023-03644-w

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