Growth arrest and spontaneous differentiation are initiated through an autocrine loop in clonally derived Schwann cells by alpha 1-procollagen IC-propeptide

Schwann cells cloned from rat sciatic nerve survive and display self-induce d growth suppression, or undergo spontaneous apoptosis, on long-term serum- free subconfluent culture. Strain SCL4.1/F7 sustained the capacity to growt h arrest for up to 40 generations. A soluble activity transmitted between n eighbouring cells of this strain suppresses DNA synthesis within three cell cycles. Autocrine Schwann cell growth-inhibitory factor (SGIF) operates du ring the G1 phase of the cell cycle, overcomes the mitogenic action of Schw ann cell/serum-associated (platelet-derived growth factor-BB) and axon-asso ciated (axolemma-enriched fraction) stimuli in serum-free conditions, and s uppresses DNA synthesis in sciatic nerve Schwann cell cultures in a stage-s pecific manner. A 35-kDa protein with N-terminal sequence and approximate m olecular mass of the C-propeptide of rat alpha 1-procollagen I makes a majo r contribution to SGIF. Growth suppression in the SCL4.1/F7 strain is media ted by the ras/extracellular signal-regulated kinase pathway, is accompanie d by down-regulation of erbB2/erbB3 and of tetraethylammonium-sensitive Kcurrents, and is followed by transition of cells within 5-10 days from O4(), p75 nerve growth factor receptor (p75NGF-R)(+), glial fibrillary acidic protein (GFAP)(+) to O4(+), p75NGF-R-, GFAP(-), periaxin(+) phenotypes. Oct -6/SCIP mRNA is present in both proliferating and growth-arrested SCL4.1/F7 cells. These results demonstrate an autocrine/paracrine loop for the growt h arrest of clonally derived Schwann cells in the absence of axons linked i n part to the metabolism of collagen. Schwann cells thus appear to self-reg ulate growth in a negative as well as a positive direction through characte rized molecular mechanisms and signal pathways.