Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53 pathway

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

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  • eLife

    eLife 10 e50346-, 2021-05

    eLife Sciences Publications

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