Disruption of entire <i>Cables2</i> locus leads to embryonic lethality by diminished <i>Rps21</i> gene expression and enhanced p53 pathway.

Abstract

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 <i>Cables2</i> locus (<i>Cables2d</i>) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of <i>Cables2</i>, 50% down-regulation of <i>Rps21</i> abutting on the <i>Cables2</i> locus, and up-regulation of p53-target genes in <i>Cables2d</i> gastrulas. We further revealed the lethality phenotype in <i>Rps21</i>-deleted mice and unexpectedly, the exon 1-deleted <i>Cables2</i> mice survived. Interestingly, chimeric mice derived from <i>Cables2d</i> ESCs carrying exogenous <i>Cables2</i> and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of <i>Rps21</i> and the completed lack of <i>Cables2</i> expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of <i>Cables2</i> locus in mouse embryonic development.