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 forelimbs 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 cones and Schwann cell precursors migrate together at the nerve front, where growth cones contact adjacent growth cones and Schwann cell precursors with similar frequency. Schwann cell precursors are extensively connected by adherens junctions and form elaborate scaffolds that enmantle growth cones at nerve fronts, so that 80% of the nerve front surface is covered by Schwann cell precursors. Although they interdigitate in complex ways among growth cones, 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 cones. This study shows for the first time that Schwann cell precursors are close and consistent cellular companions of growth cones in their approach to their final targets in the developing limb and suggests a previously unappreciated role for Schwann cell precursors in growth cone advance through the limb mesenchyme. V C 2006 Wiley-Liss, Inc.