Growth arrest and spontaneous differentiation are initiated through an autocrine loop in clonally derived Schwann cells by alpha1-procollagen I C-propeptide.
Schwann cells cloned from rat sciatic nerve survive and display self-induced growth suppression, or undergo spontaneous apoptosis, on long-term serum-free subconfluent culture. Strain SCL4.1/F7 sustained the capacity to growth arrest for up to 40 generations. A soluble activity transmitted between neighbouring cells of this strain suppresses DNA synthesis within three cell cycles. Autocrine Schwann cell growth-inhibitory factor (SGIF) operates during the G1 phase of the cell cycle, overcomes the mitogenic action of Schwann cell/serum-associated (platelet-derived growth factor-BB) and axon-associated (axolemma-enriched fraction) stimuli in serum-free conditions, and suppresses DNA synthesis in sciatic nerve Schwann cell cultures in a stage-specific manner. A 35-kDa protein with N-terminal sequence and approximate molecular mass of the C-propeptide of rat alpha1-procollagen I makes a major contribution to SGIF. Growth suppression in the SCL4.1/F7 strain is mediated by the ras/extracellular signal-regulated kinase pathway, is accompanied by down-regulation of erbB2/erbB3 and of tetraethylammonium-sensitive K+ currents, 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 growth arrest of clonally derived Schwann cells in the absence of axons linked in part to the metabolism of collagen. Schwann cells thus appear to self-regulate growth in a negative as well as a positive direction through characterized molecular mechanisms and signal pathways.
Rushton
J A
JA
School of Biological Sciences, University of Bristol, England.
Schmitz
S
S
Gunn-Moore
F
F
Sherman
D
D
Pappas
C A
CA
Ritchie
J M
JM
Haynes
L W
LW
D000818:Animals; D000077214:Becaplermin; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004247:DNA / Q000096:biosynthesis; D016193:G1 Phase; D006131:Growth Inhibitors / Q000032:analysis / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D009186:Myelin Sheath / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011347:Procollagen / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036143:Receptor, EphA8; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology* / Q000187:drug effects; D012584:Sciatic Nerve / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D000077214:Becaplermin; D017077:Culture Media, Conditioned; D004247:DNA; D006131:Growth Inhibitors; D008934:Mitogens; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D015221:Potassium Channels; D011347:Procollagen; D020574:Proto-Oncogene Proteins c-sis; D020794:Receptor Protein-Tyrosine Kinases; D036143:Receptor, EphA8; D018719:Erb-b2 Receptor Tyrosine Kinases; C042813:procollagen type I carboxy terminal peptide