Open AccessSynergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
Author(s) -
Shunbin Xiong,
Carolyn S. Van Pelt,
Ana C. Elizondo-Fraire,
Geng Li,
Guillermina Lozano
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0508500103
Subject(s) - mdm2 , biology , phenotype , embryonic stem cell , transgene , allele , gene , genetics , loss function , apoptosis , cancer research , microbiology and biotechnology
Loss ofMdm2 orMdm4 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 deleteMdm2 andMdm4 in the CNS. Mice lackingMdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereasMdm4 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 andMdm4 had a gene dosage effect, because loss of three of the fourMdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone. All phenotypes were rescued by deletion ofp53 . Thus, thesein vivo data demonstrate the importance of Mdm4 independent of Mdm2 in inhibition of p53.