Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that arep53-dependent. To determine whether Mdm2 and Mdm4 inhibitp53 function redundantly in a more restricted cell type, conditionalalleles were crossed to a neuronal specific Cre transgene to deleteMdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNSdeveloped hydranencephaly at embryonic day 12.5 due to apoptosis,whereas Mdm4 deletion showed a proencephaly phenotypeat embryonic day 17.5 because of cell cycle arrest andapoptosis. The deletion of both genes, strikingly, contributed to aneven earlier and more severe CNS phenotype. Additionally, Mdm2and Mdm4 had a gene dosage effect, because loss of three of thefour Mdm alleles also showed a more accelerated CNS phenotypethan deletion of either gene alone. All phenotypes were rescued bydeletion of p53. Thus, these in vivo data demonstrate the importanceof Mdm4 independent of Mdm2 in inhibition of p53