p63 antagonizes p53 to promote the survival of embryonic neural precursor cells.
The molecular mechanisms that regulate survival of embryonic neural precursors are still relatively ill-defined. Here, we have asked whether the p53 family member p63 plays any role during this developmental window, focusing on the embryonic cerebral cortex. We show that genetic knockdown of p63 either in culture or in the embryonic telencephalon causes apoptosis of cortical precursors and newly born cortical neurons, and that this can be rescued by expression of DeltaNp63, but not TAp63 isoforms. This cortical precursor apoptosis is the consequence of deregulated p53 activity, since both basal precursor apoptosis and that induced by loss of p63 are rescued by coincident genetic silencing of p53. Finally, we demonstrate that the third p53 family member, DeltaNp73, does not regulate survival of cortical precursor cells, but that it collaborates with DeltaNp63 to ensure the survival of newly born cortical neurons. Thus, the balance of DeltaNp63 versus p53 determines the life versus death of embryonic cortical precursors, a role that these p53 family members may well play in other populations of developing and/or adult neural precursors.
Dugani
Chandrasagar B
CB
Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Paquin
Annie
A
Fujitani
Masashi
M
Kaplan
David R
DR
Miller
Freda D
FD
D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D004268:DNA-Binding Proteins / Q000172:deficiency; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency; D010750:Phosphoproteins / Q000502:physiology*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D014404:Tubulin; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053148:Caspase 3