TY - JOUR
T1 - Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
AU - Xiong, Shunbin
AU - Van Pelt, Carolyn S.
AU - Elizondo-Fraire, Ana C.
AU - Liu, Geng
AU - Lozano, Guillermina
PY - 2006/2/28
Y1 - 2006/2/28
N2 - Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent. To determine whether Mdm2 and Mdm4 inhibit p53 function redundantly in a more restricted cell type, conditional alleles were crossed to a neuronal specific Cre transgene to delete Mdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereas Mdm4 deletion showed a proencephaly phenotype at embryonic day 17.5 because of cell cycle arrest and apoptosis. The deletion of both genes, strikingly, contributed to an even earlier and more severe CNS phenotype. Additionally, Mdm2 and Mdm4 had a gene dosage effect, because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone. All phenotypes were rescued by deletion of p53. Thus, these in vivo data demonstrate the importance of Mdm4 independent of Mdm2 in inhibition of p53.
AB - Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent. To determine whether Mdm2 and Mdm4 inhibit p53 function redundantly in a more restricted cell type, conditional alleles were crossed to a neuronal specific Cre transgene to delete Mdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereas Mdm4 deletion showed a proencephaly phenotype at embryonic day 17.5 because of cell cycle arrest and apoptosis. The deletion of both genes, strikingly, contributed to an even earlier and more severe CNS phenotype. Additionally, Mdm2 and Mdm4 had a gene dosage effect, because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone. All phenotypes were rescued by deletion of p53. Thus, these in vivo data demonstrate the importance of Mdm4 independent of Mdm2 in inhibition of p53.
KW - Apoptosis
KW - Cell cycle arrest
KW - Conditional alleles
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U2 - 10.1073/pnas.0508500103
DO - 10.1073/pnas.0508500103
M3 - Article
C2 - 16492743
AN - SCOPUS:33644757727
SN - 0027-8424
VL - 103
SP - 3226
EP - 3231
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -