Ablation of Lrp4 in Schwann Cells Promotes Peripheral Nerve Regeneration in Mice

SIMPLE SUMMARY: Schwann cells (SCs) are the primary glial cells in the peripheral nervous system and play an indispensable role in peripheral nerve regeneration. A recent study indicated the potential involvement of low-density lipoprotein receptor-related protein 4 (Lrp4) in axonal regeneration in larval zebrafish. However, whether Lrp4 participates in nerve regeneration in mammals remains unknown. Herein, we constructed conditional knockout (cKO) mice in which Lrp4 was specifically deleted in SCs under the control of the Dhh-cre promoter. We found that the peripheral nerve regeneration in cKO mice was more robust than that in control mice. Assessment of SC proliferation via BrdU staining revealed significantly increased cell numbers in the cKO mice. Furthermore, as a master transcription factor participating in the onset of myelination, Krox-20 was dramatically downregulated in the injured nerves of the cKO group compared with the control group nerves. The enhanced demyelination speed in cKO mice was confirmed by electron microscopy. Altogether, these results suggest that Krox-20 downregulation in mutant mice leads to SC proliferation upon injury and that SCs can remove myelin debris, thereby promoting nerve regeneration. ABSTRACT: Low-density lipoprotein receptor-related protein 4 (Lrp4) is a critical protein involved in the Agrin-Lrp4-MuSK signaling pathway that drives the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). Many studies have shown that Lrp4 also functions in kidney development, bone formation, nervous system development, etc. However, whether Lrp4 participates in nerve regeneration in mammals remains unknown. Herein, we show that Lrp4 is expressed in SCs and that conditional knockout (cKO) of Lrp4 in SCs promotes peripheral nerve regeneration. In Lrp4 cKO mice, the demyelination of SCs was accelerated, and the proliferation of SCs was increased in the injured nerve. Furthermore, we identified that two myelination-related genes, Krox-20 and Mpz, were downregulated more dramatically in the cKO group than in the control group. Our results elucidate a novel role of Lrp4 in peripheral nerve regeneration and thereby provide a potential therapeutic target for peripheral nerve recovery.