Neural cell adhesion molecule (N-CAM) domains and intracellular signaling pathways involved in the inhibition of astrocyte proliferation.
The neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation in vitro and in vivo, and this effect is partially reversed by the glucocorticoid antagonist RU-486. The present studies have tested the hypothesis that N-CAM-mediated inhibition of astrocyte proliferation is caused by homophilic binding and involves the activation of glucocorticoid receptors. It was observed that all N-CAM Ig domains inhibited astrocyte proliferation in parallel with their ability to influence N-CAM binding. The proliferation of other N-CAM-expressing cells also was inhibited by the addition of N-CAM. In contrast, the proliferation of astrocytes from knockout mice lacking N-CAM was not inhibited by added N-CAM. These findings support the hypothesis that it is binding of soluble N-CAM to N-CAM on the astrocyte surface that leads to decreased proliferation. Signaling pathways stimulated by growth factors include activation of mitogen-activated protein (MAP) kinase. Addition of N-CAM inhibited MAP kinase activity induced by basic fibroblast growth factor in astrocytes. In accord with previous findings that RU-486 could partially prevent the proliferative effects of N-CAM, inhibition of MAP kinase activity by N-CAM was reversed by RU-486. The ability of N-CAM to inhibit astrocyte proliferation was unaffected, however, by agents that block the ability of N-CAM to promote neurite outgrowth. Together, these findings indicate that homophilic N-CAM binding leads to inhibition of astrocyte proliferation via a pathway involving the glucocorticoid receptor and that the ability of N-CAM to influence astrocyte proliferation and neurite outgrowth involves different signal pathways.
Krushel
L A
LA
Department of Neurobiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tai
M H
MH
Cunningham
B A
BA
Edelman
G M
GM
Crossin
K L
KL
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005910:Glioma; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D004247:DNA