Invariant mantling of growth cones by Schwann cell precursors characterize growing peripheral nerve fronts.

Little is known about the cytoarchitecture of growth fronts in developing mammalian nerves. We report here the first quantitative, ultrastructural analysis of growth cones (GCs) and their immediate cellular and tissue environment at tips of growing nerves that are nearing their targets in fore limbs of E14 rat embryos. Schwann cell precursor (SCP) marker, p75 neurotrophin receptor, and growth cone marker, SCG10, were used to identify nerve fronts, respectively. Using confocal 3D reconstructions and immunoelectron microscopy, we found that growth cone and Schwann cell precursor migrate together at the nerve front, where growth cone contact adjacent growth cone and Schwann cell precursor with similar frequency. Schwann cell precursor are extensively connected by adherens junctions and form elaborate scaffolds that enmantle growth cone at nerve fronts, so that 80% of the nerve front surface is covered by Schwann cell precursor. Although they interdigitate in complex ways among growth cone, the total contact area between growth cone and glial membranes is remarkably constant among the 100 growth fronts analyzed. In contrast to this consistency, other growth cone contacts varied markedly from front to front such that the frequencies of GC-GC contacts are increasing proportional to their decreasing contacts with mesenchymal tissue. Thus, at the nerve front, it is the Schwann cell precursor that are most exposed to extracellular environment while forming a surprisingly invariant substrate for advancing growth cone. This study shows for the first time that Schwann cell precursor are close and consistent cellular companions of growth cone in their approach to their final targets in the developing limb and suggests a previously unappreciated role for Schwann cell precursor in growth cone advance through the limb mesenchyme.