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Alternative splicing of the MAPT 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\u22124R, LMW\u22124R, HMW\u22123R, and LMW\u22123R 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\u2212tau isoforms were more effective than the 4R\u2212tau 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.<\/jats:p>","DOI":"10.3390\/ijms252212352","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T05:36:45Z","timestamp":1731908205000},"page":"12352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tau Isoform-Regulated Schwann Cell Proliferation and Migration Improve Peripheral Nerve Regeneration After Injury"],"prefix":"10.3390","volume":"25","author":[{"given":"Shiying","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guifang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2818-8511","authenticated-orcid":false,"given":"Qianyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghui","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-4267","authenticated-orcid":false,"given":"Qianqian","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5661-9051","authenticated-orcid":false,"given":"Dandan","family":"Chu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0166-2236(91)90105-4","article-title":"Molecular characterization of microtubule-associated proteins tau and MAP2","volume":"14","author":"Goedert","year":"1991","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/0896-6273(89)90210-9","article-title":"Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer\u2019s disease","volume":"3","author":"Goedert","year":"1989","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.tins.2020.04.007","article-title":"Resurrecting the Mysteries of Big Tau","volume":"43","author":"Fischer","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/cne.903580209","article-title":"Distribution of Big tau in the central nervous system of the adult and developing rat","volume":"358","author":"Boyne","year":"1995","journal-title":"J. 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