Sonic hedgehog promotes Schwann cell proliferation through PI3K/AKT/cyclin E1 pathway

The proliferation of Schwann cells (SCs) is essential for both the development and regeneration of peripheral nervous system (PNS). Sonic hedgehog (Shh), a multifunctional signaling protein, plays pivotal roles in pattern formation, cell proliferation and cell survival during embryogenesis and tissue repair. While up-regulation of Shh in neurons and SCs following peripheral nerve injury has been associated with enhanced nerve regeneration its specific regulatory effects on SC proliferation remain poorly defined. In this study, we demonstrate dual expression patterns of Shh: significant up regulation in repair SCs post-injury and sustained high expression in immature SCs during developmental stages. Through lentivirus-mediated Shh knockdown in cultured SCs, we revealed that Shh silencing markedly suppresses SC proliferation by inducing G2/M-phase arrest. Transcriptomic profiling identified cell cycle dysregulation upon Shh depletion, characterized by diminished cyclin E1 expression. In mechanism, Shh maintains proliferative capacity through PI3K/AKT signaling activation, as evidenced by pathway inhibition following Shh silencing and subsequent rescue of proliferation deficits with PI3K/AKT agonists. These findings establish the PI3K/AKT/cyclin E1 axis as a central mechanism underlying Shh-mediated SC proliferation control. Our work elucidates the dual regulatory role of Shh in developmental and regenerative contexts while highlighting its potential as a therapeutic target for inherited peripheral neuropathies and peripheral nerve repair.