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Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons

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Abstract

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.

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Acknowledgements

We thank Dr. Naihe Jing (Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences) for discussing this project, and Beibei Wang (Center of Cryo-Electron Microscopy, Zhejiang University) for technical support. We are also grateful to Samuel L. Pfaff (The Salk Institute for Biological Studies) for providing reagents. This work was supported by the Zhejiang Provincial Natural Science Foundation of China (LY19H090030), the Science and Technology Innovation 2030-Major Project of Brain Science and Brain-like Research (2021ZD0202501), the Excellent Innovation Program of Hangzhou Municipal University in 2019, and the National Natural Science Foundation of China (82150003, 91949104, and 31871022).

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Author notes

  1. Weiping Pan, Xueyin Huang, and Zikai Yu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Zhejiang University City College, Hangzhou, 310015, China

    Weiping Pan, Zikai Yu, Qiongqiong Ding, Qisong Xiong, Hualin Yu, Junbo Wang, Linghui Zeng & Huaqing Liu

  2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Weiping Pan, Zikai Yu, Qisong Xiong & Hualin Yu

  3. Department of Neurobiology and Department of Neurology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Xueyin Huang, Jianfeng Hua, Bokai Gu & Ge Bai

  4. Department of Anesthesiology and Department of Neurobiology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Liping Xia & Zhenzhong Xu

  5. Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, 311121, China

    Ge Bai

  6. NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, 310058, China

    Ge Bai

  7. Institute of Brain and Cognition, Zhejiang University City College School of Medicine, Hangzhou, 310015, China

    Ge Bai & Huaqing Liu

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  1. Weiping Pan
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Pan, W., Huang, X., Yu, Z. et al. Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons. Neurosci. Bull. 39, 745–758 (2023). https://doi.org/10.1007/s12264-022-01011-8

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