ReviewThe nerve regenerative microenvironment: Early behavior and partnership of axons and Schwann cells

This review will address new ideas, including several from our laboratory, on the role of local molecules and signaling within the microenvironment of injured peripheral nerve trunks. These include the concepts of axon-Schwann cell (SC) outgrowth partnership such as the secretion of local molecules that may facilitate or inhibit regenerative activity and the role of directional cues secreted by the SCs to guide regrowing axons. Several specific themes along these lines are explored: (i) a role for peptidergic axon synthesis and signaling to SCs; (ii) the expression of molecular regeneration brakes in regenerating axons, specifically activated RHOA GTPase; (iii) the concept of misdirected axon outgrowth, focusing on the prototypic NGF and local TrkA interaction in adult regrowth; (iv) the role of extracellular basement membrane constituents such as laminin, RGD/fibronectin and their integrin receptors. We show that these different themes play an important but not exclusive role in determining regenerative success. Collectively, these individual findings help us appreciate the many facets of regenerative success which depend on the surrounding environment, the expressed receptors, and the internal state of the growing axon.