title: Conditional ablation of p63 indicates that it is essential for embryonic development of the central nervous system.
abstract: p63 is a member of the p53 family that regulates the survival of neural precursors in the adult brain. However, the relative importance of p63 in the developing brain is still unclear, since embryonic p63(-/-) mice display no apparent deficits in neural development. Here, we have used a more definitive conditional knockout mouse approach to address this issue, crossing p63(fl/fl) mice to mice carrying a nestin-CreERT2 transgene that drives inducible recombination in neural precursors following tamoxifen treatment. Inducible ablation of p63 following tamoxifen treatment of mice on embryonic day 12 resulted in highly perturbed forebrain morphology including a thinner cortex and enlarged lateral ventricles 3 d later. While the normal cortical layers were still present following acute p63 ablation, cortical precursors and neurons were both reduced in number due to widespread cellular apoptosis. This apoptosis was cell-autonomous, since it also occurred when p63 was inducibly ablated in primary cultured cortical precursors. Finally, we demonstrate increased expression of the mRNA encoding another p53 family member, ΔNp73, in cortical precursors of p63(-/-) but not tamoxifen-treated p63(fl/fl);R26YFP(fl/fl);nestin-CreERT2(+/Ø) embryos. Since ΔNp73 promotes cell survival, then this compensatory increase likely explains the lack of an embryonic brain phenotype in p63(-/-) mice. Thus, p63 plays a key prosurvival role in the developing mammalian brain.
authors.affiliation: a Program in Neurosciences and Mental Health, Hospital for Sick Children ; Toronto , ON Canada.
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.affiliation: a Program in Neurosciences and Mental Health, Hospital for Sick Children ; Toronto , ON Canada.|b Institute of Medical Science, University of Toronto ; Toronto , ON Canada.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fatt
authors.affiliation: a Program in Neurosciences and Mental Health, Hospital for Sick Children ; Toronto , ON Canada.|b Institute of Medical Science, University of Toronto ; Toronto , ON Canada.|c Departments of Physiology ; University of Toronto ; Toronto , ON Canada.|d Molecular Genetics, University of Toronto ; Toronto , ON Canada.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: a Program in Neurosciences and Mental Health, Hospital for Sick Children ; Toronto , ON Canada.|b Institute of Medical Science, University of Toronto ; Toronto , ON Canada.|d Molecular Genetics, University of Toronto ; Toronto , ON Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000196:embryology* / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics; D011247:Pregnancy; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse
keywords: apoptosis; cortex; intermediate progenitors; neural precursor cells; neural stem cells; neurogenesis; p53; p63; p73; radial glial cells