Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons.
GAP-43 is first expressed in proliferating neuroblasts and is required for maturation of neurons. When GAP-43 is not expressed in differentiating embryonal carcinoma P19 cells, reduced numbers of neurons were generated. Here we show that neuronal differentiation is initially disrupted at the onset of cell-cycle arrest in aggregated, proliferating neuronal precursors. The ratio of nestin:beta-tubulin-labeled progeny generated at this stage suggests that the differentiation is asymmetric. Apoptosis of immature neurons subsequently produced was also significantly induced. In vivo, too, proliferation of neuroblasts was significantly reduced in cortex of GAP-43(-/-) mice at E14.5. These data demonstrate that when GAP-43 is not expressed in proliferating neuroblasts, neural differentiation is not initiated appropriately, inducing apoptosis. Moreover, the concurrent inhibition of Ca2+-dependent adhesion between differentiating P19 cells in aggregates implicates GAP-43 in CAM-mediated signaling during neurogenesis, as has been previously shown in growth cones.
Mani
S
S
Program in Neuroscience, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Shen
Y
Y
Schaefer
J
J
Meiri
K F
KF
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D002999:Clone Cells; D054278:Embryonal Carcinoma Stem Cells; D019922:GAP-43 Protein / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins; D064231:Nestin; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology
D019922:GAP-43 Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D014212:Tretinoin; D002118:Calcium