Involvement of p53 and Fas/CD95 in murine neural progenitor cell response to ionizing irradiation.
We investigated the role of tumor suppressor p53 and Fas (CD95/APO-1), a member of the tumor necrosis factor receptor family, in neural progenitors response to gamma-irradiation exposure. Telencephalic cells were obtained from wild-type C57Bl/6, or p53-/- or fas-/-, 15-day-old mouse embryos. They were cultured in conditions allowing neural progenitors to form proliferating clusters (neurospheres). A 2 Gy gamma-irradiation induced a G1 cell cycle arrest and triggered apoptosis in wild-type neural progenitor cultures in correlation with an enhanced expression of p53 and of its downstream target p21(WAF1), both of them acquiring a nuclear localization. These effects did not occur in p53-/- neural progenitors demonstrating the central role played by p53 in their response to ionizing radiation. Furthermore, the monoclonal antibody Jo2 directed against Fas induced apoptosis of wild type but not of fas-/- neural progenitors, indicating the existence of a functional Fas signaling pathway in neural progenitors. Ionizing radiation induced an increase of Fas membrane expression related to a p53-dependent increase of fas mRNA expression in wild-type neural progenitors. Moreover, fas-/- neural progenitors exhibited delayed radiation-induced apoptosis compared to wild-type cells. Therefore, these findings establish a role for Fas/CD95 related to p53 in the response of neural progenitors to gamma-radiation exposure. Similar mechanisms could be triggered in neural progenitors in case of different stresses during brain development or in the course of various diseases affecting the adult brain.
Semont
Alexandra
A
Laboratoire de RadioPathologie, DRR/DSV, CEA, IPSC, Fontenay-aux-Roses, France.
Nowak
Ewa B
EB
Silva Lages
Céline
C
Mathieu
Céline
C
Mouthon
Marc-André
MA
May
Evelyne
E
Allemand
Isabelle
I
Millet
Pascal
P
Boussin
François D
FD
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
C491899:Fas protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor