Low-density lipoprotein receptor-related proteins guide navigating PNS axons

The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1, LRP2) are emerging as important cell signalling mediators in modulating neuronal growth. We asked whether the LRP1 or LRP2 receptors are able to mediate a specific aspect of neuronal growth in the PNS: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemo-attraction, which may have therapeutic potential. We used embryonic sensory neurons from the dorsal root ganglia in the growth cone turning assays to test a range of LRP1 and LRP2 ligands for their ability to guide growth cone navigation. The regenerative ability of LRP-mediated chemo-attraction was also examined in vivo in a model of capsaicin induced chemical denervation in adult rats. Three ligands were chemo-repulsive, a2- macroglobulin, tissue plasminogen activator and metallothionein III, while only one LRP ligand, metallothionein II, was found to be chemo-attractive. Chemo-attraction towards a gradient of metallothionein II was abolished by LRP-receptor inhibition or reduced LRP1 or LRP2 expression and was calcium dependent. In the in vivo studies, metallothionein II was shown to enhance regeneration after complete capsaicin induced dermal denervation, such that regeneration was complete within 7 days, compared to 14 days in the saline treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II mediated chemotactic signal transduction, and may form part of a signalling complex. Furthermore, the data suggest that LRP-mediated chemo-attraction represents a novel, non-classical signalling system, which has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.