Glial cell line-derived neurotrophic factor-induced signaling in Schwann cells.
Glial cell line-derived neurotrophic factor (GDNF), a known survival factor for neurons, has recently been shown to stimulate the migration of Schwann cells (SCs) and to enhance myelination. GDNF exerts its biological effects by activating the Ret tyrosine kinase in the presence of glycosylphosphatidylinositol-linked receptor, GDNF family receptor (GFR) alpha1. In Ret-negative cells, the alternative transmembrane coreceptor is the 140-kDa isoform of neural cell adhesion molecule (NCAM) associated with a non-receptor tyrosine kinase Fyn. We confirmed that GDNF, GFRalpha1 and NCAM are expressed in neonatal rat SCs. We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNF-signaling in SCs. In addition to activation of extracellular signal-regulated kinases, and phosphorylation of cAMP response element binding protein, we found that cAMP-dependent protein kinase A and protein kinase C are involved in GDNF-mediated signaling in SCs. Although GDNF did not promote the differentiation of purified SCs into the myelinating phenotype, it enhanced myelination in neuron-SC cocultures. We conclude that GDNF utilizes NCAM signaling pathways to regulate SC function prior to myelination and at early stages of myelin formation.
Iwase
T
T
Department of Neurology and Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Jung
C G
CG
Bae
H
H
Zhang
M
M
Soliven
B
B
D018171:Agrin / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D021962:Membrane Microdomains / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018171:Agrin; D017362:Cyclic AMP Response Element-Binding Protein; C495041:Gdnf protein, rat; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D019006:Neural Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C495001:Ret protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C