Tau Isoform-Regulated Schwann Cell Proliferation and Migration Improve Peripheral Nerve Regeneration After Injury

Tau is a microtubule-associated protein that plays a vital role in the mammalian nervous system. Alternative splicing of the <i>MAPT</i> 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.