Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China.
Int J Mol Sci. 2024 Nov 18;25(22):12352. doi: 10.3390/ijms252212352.
Tau is a microtubule-associated protein that plays a vital role in the mammalian nervous system. Alternative splicing of the gene leads to the formation of tau isoforms with varying N-terminal inserts and microtubule-binding repeats. Dysregulation of tau alternative splicing has been linked to diseases in the central nervous system, but the roles of tau isoforms in the peripheral nervous system remain unclear. Here, we investigated the alternative splicing of tau exons 4A and 10 in the sciatic nerve and Schwann cells during development and following injury. We discovered that low-molecular-weight (LMW) tau, resulting from the exclusion of exon 4A, and 3R tau, generated by the exclusion of exon 10, diminishes with aging in rat sciatic nerve and Schwann cells. High-molecular-weight (HMW) tau and 3R tau increase in the adult sciatic nerve post-injury. We constructed viruses that expressed HMW-4R, LMW-4R, HMW-3R, and LMW-3R and introduced them into cultured cells or the distal part of the injured sciatic nerve to assess their effects on Schwann cell migration and proliferation. We also examined the effects of the four isoforms on axon growth and debris clearance after sciatic nerve injury. Our results demonstrated that tau isoforms inhibit Schwann cell proliferation while promoting Schwann cell migration and sciatic nerve regeneration. Specifically, the 3R-tau isoforms were more effective than the 4R-tau isoforms in promoting nerve regeneration. In conclusion, our study reveals the roles of tau isoforms in the peripheral nervous system and provides insights into the development of new therapeutic strategies for peripheral nerve injuries.
tau 是一种微管相关蛋白，在哺乳动物神经系统中发挥着至关重要的作用。该基因的选择性剪接导致形成具有不同 N 端插入和微管结合重复的 tau 同工型。tau 选择性剪接的失调与中枢神经系统疾病有关，但 tau 同工型在周围神经系统中的作用尚不清楚。在这里，我们研究了在发育过程中和损伤后坐骨神经和雪旺细胞中 tau 外显子 4A 和 10 的选择性剪接。我们发现，低分子量（LMW）tau 由外显子 4A 的缺失产生，而 3R tau 由外显子 10 的缺失产生，在大鼠坐骨神经和雪旺细胞中随年龄的增长而减少。高分子量（HMW）tau 和 3R tau 在成年坐骨神经损伤后增加。我们构建了表达 HMW-4R、LMW-4R、HMW-3R 和 LMW-3R 的病毒，并将其引入培养的细胞或损伤的坐骨神经远端，以评估它们对雪旺细胞迁移和增殖的影响。我们还研究了这四种同工型对坐骨神经损伤后轴突生长和碎片清除的影响。我们的结果表明，tau 同工型抑制雪旺细胞增殖，同时促进雪旺细胞迁移和坐骨神经再生。具体而言，3R-tau 同工型比 4R-tau 同工型更有效地促进神经再生。总之，我们的研究揭示了 tau 同工型在周围神经系统中的作用，并为周围神经损伤的新治疗策略的发展提供了思路。
