Substrate interactions affecting motor growth cone guidance during development and regeneration

Most serious injuries of spinal nerves or roots in man and other higher vertebrates lead to permanent loss of control of skeletal muscles. In some cases this may be due to a failure of motor axons to regenerate, although even when functional neuromuscular connections are re-established, coordinated use of body and limb muscles may be absent. In both mammals and lower vertebrates, damaged motor axons usually regrow and reform functional connections with muscles, although these connections are often inappropriate. The selectivity of reinnervation is improved by maintaining alignment of the severed ends of the nerve. Thus, factors operating near the lesion site may direct regenerating motor axons into fascicles in the distal nerve stump that lead to inappropriate muscles. The identity of some of these factors is suggested by recent studies of developing systems which have shown that motor axons are directed in their growth. (a) The filopodia of their growth cones sample a limited region of the periphery. If motor growth cones extend too far from their normal pathways they establish connections with inappropriate muscles. (b) Motor growth cones normally extend into regions of embryos rich in the extracellular matrix molecule laminin, and avoid regions containing fibronectin. Moreover, motor growth cones extend on laminin but not on fibronectin substrates in vitro. In peripheral nerves, these two molecules are differentially distributed; laminin is expressed by Schwann cells in the endoneurium whereas fibronectin is expressed by fibroblasts primarily in the perineurium. These studies suggest that regenerating motor growth cones may be directed to appropriate muscles if their original fascicles within the distal nerve stump are within filopodial reach but may not be able to escape the fibronectin-rich perineurial sheath once directed into an inappropriate fascicle.