In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire locus ( ) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of , 50% down-regulation of abutting on the locus, and up-regulation of p53-target genes in gastrulas. We further revealed the lethality phenotype in -deleted mice and unexpectedly, the exon 1-deleted mice survived. Interestingly, chimeric mice derived from ESCs carrying exogenous and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of and the completed lack of expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of locus in mouse embryonic development.