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Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53
Tra Thi Huong Dinh1,2,3,4, Hiroyoshi Iseki1,5, Seiya Mizuno1,4
1Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
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 Cables2 locus (Cables2d) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of Cables2, 50% down-regulation of Rps21 abutting on the Cables2 locus, and up-regulation of p53-target genes in Cables2d gastrulas. We further revealed the lethality phenotype in Rps21-deleted mice and unexpectedly, the exon 1-deleted Cables2 mice survived. Interestingly, chimeric mice derived from Cables2d ESCs carrying exogenous Cables2 and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of Rps21 and the completed lack of Cables2 expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of Cables2 locus in mouse embryonic development.
Insights
Disrupting the Cables2 locus in mice caused embryonic lethality due to reduced Rps21 expression and lack of Cables2, impacting the p53 pathway during development.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- The in vivo function of CDK5 and Abl enzyme substrate 2 (Cables2) is unknown.
- Cables2 belongs to the Cables protein family, with its precise role in embryonic development uncharacterized.
Purpose of the Study:
- To investigate the in vivo function of Cables2 during mouse embryonic development.
- To elucidate the molecular mechanisms underlying embryonic lethality associated with Cables2 locus disruption.
Main Methods:
- Targeted disruption of the entire Cables2 locus (Cables2d) in mice.
- Comparative transcriptome analysis of Cables2d gastrulas.
- Generation and analysis of Rps21-deleted and exon 1-deleted Cables2 mice.
- Construction of chimeric mice using Cables2d ESCs.
Main Results:
- Cables2d mice exhibited growth retardation, enhanced apoptosis at gastrulation, and embryonic lethality.
- Transcriptome analysis revealed Cables2 disruption, Rps21 down-regulation, and p53-target gene up-regulation in Cables2d gastrulas.
- Rps21 deletion caused lethality, while exon 1 deletion of Cables2 did not, suggesting a complex genetic interaction.
Conclusions:
- Diminished Rps21 expression and complete lack of Cables2 are intricately involved in embryonic lethality via the p53 pathway.
- The Cables2 locus plays a critical role in mouse embryonic development, with implications for both Cables2 and adjacent gene regulation.
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