A molecular study of the signals that control Schwann cell development and myelination in vivo
To identify novel genes that may be involved in Schwann cell lineage development and in myelination, we combined microarray based gene expression profiling with a refined bioinformatic analysis. We compared mRNA from rat sciatic nerves at embryonic day 14 (El4), El8, postnatal day 7 (P7), P12 and in the distal stump of PI2 sciatic nerves cut five days previously and in which, therefore, all the myelin related genes should be strongly down-regulated. 1609 genes and expressed sequence tags (ESTs) were found to have at least a two-fold change in their level of expression either during development or after nerve injury. On this set of genes/ESTs a statistical analysis was performed to identify those that were significantly different between two time points. This was then followed by a sequence mapping and a protein structural and functional annotation carried out with Biopendium software, which enabled us to substantially minimise the number of unknown sequences. We identified agrin and two members of the collapsin response mediated protein family (CRMP) as possibly involved in the transition between Schwann cell precursors (El4) and immature Schwann cells (El8). Our data also suggest that the cartilage related proteins type II collagen and chondromodulin-1, and the cytoskeletal protein synuclein-1 may have important functions during peripheral nerve myelination. In addition, to clarify the role of transforming growth factor beta (TGFP) during Schwann cell development in vivo, mice carrying a floxed segment of the TGF 3 type II receptor have been crossed with mice in which the CRE recombinase is expressed under the control of the P0 myelin protein promoter. Although myelination appears to occur normally, we found that Schwann cells death and proliferation rate are impaired in the perinatal period, both during normal development and after nerve injury, indicating a key role for TGF 3 in controlling these events.