It is all about the support - The role of the extracellular matrix in regenerating axon guidance.

Although it is known for long time that the peripheral nervous system has the capacity for self-regeneration, the molecular mechanisms by which Schwann cells and extracellular matrix (ECM) guide the injured axons to regrow along their original path, remains a poorly understood process. Due to the importance of ECM molecules during development, constitutive mutant organisms display increased lethality, therefore, conditional or inducible strategies have been used to increase the survival of the organisms and allow the study of the role of ECM proteins. In a recent report published in Neuron, Isaacman-Beck and colleagues (2015) used these pioneering genetic studies on zebrafish combined with in vivo fluorescent imaging, to investigate the micro-environmental conditions required for targeted regeneration of the dorsal motor nerve of zebrafish larvae after laser-transection. A candidate gene approach targeting lh3 basal laminar collagen substrates revealed that the lh3 substrate col4α5 regulates dorsal nerve regeneration by destabilizing misdirected axons. Col4α5 was upregulated in a small population of lh3 expressing Schwann cells located ventrally and ventro-laterally to the injury site and found to co-localize with the molecule slit guidance ligand 1 (slit1a). Capitalizing on the crucial observations of mistargeted regeneration of dorsal nerves in mutant larvae, they put forward a model in which Schwann cells shape an environment that allows and directs axonal regeneration to their original synaptic target. In the light of Isaacman-Beck and colleagues (2015) findings, we will review how their study contributes to the research field, and comment on its potential implications for promoting nerve regeneration after injury.