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Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice.

ABSTRACT: CIZ1 plays a role in DNA synthesis at the G1/S checkpoint. Ciz1 gene-trap null mice manifest motor dysfunction, cell-cycle abnormalities, and DNA damage. In contrast, it has previously been reported that mouse embryonic fibroblasts derived from presumed Ciz1 knock-out mice (Ciz1tm1.1Homy/tm1.1Homy ) generated by crossing Cre-expressing mice with exon 5-floxed mice (Ciz1tm1Homy/tm1Homy ) do not exhibit evidence of enhanced DNA damage following ?-irradiation or cell-cycle defects. Here, we report that Ciz1tm1.1Homy/tm1.1Homy mice show loss of Ciz1 exon 5 but are neurologically normal and express abnormal transcripts (Ciz1?E5/?E5 mice) that are translated into one or more proteins of approximate wild-type size. Therefore, Ciz1tm1.1Homy/tm1.1Homy mice (Ciz1?E5/?E5 ) lose residues encoded by exon 5 but may gain function from novel amino acid sequences.

SUBMITTER: Xiao J

PROVIDER: S-EPMC6275157 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice.

Xiao Jianfeng J Khan Mohammad Moshahid MM Vemula Satya S Tian Jun J LeDoux Mark S MS

FEBS letters 20180829 18

CIZ1 plays a role in DNA synthesis at the G1/S checkpoint. Ciz1 gene-trap null mice manifest motor dysfunction, cell-cycle abnormalities, and DNA damage. In contrast, it has previously been reported that mouse embryonic fibroblasts derived from presumed Ciz1 knock-out mice (Ciz1<sup>tm1.1Homy/tm1.1Homy</sup> ) generated by crossing Cre-expressing mice with exon 5-floxed mice (Ciz1<sup>tm1Homy/tm1Homy</sup> ) do not exhibit evidence of enhanced DNA damage following γ-irradiation or cell-cycle def ...[more]

PMID: 30098009

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Project description:Administration of active growth differentiation factor 11 (GDF11) to aged mice can reduce cardiac hypertrophy, and low serum levels of GDF11 measured together with the related protein, myostatin (also known as GDF8), predict future morbidity and mortality in coronary heart patients. Using mice with a loxP-flanked ("floxed") allele of Gdf11 and Myh6-driven expression of Cre recombinase to delete Gdf11 in cardiomyocytes, we tested the hypothesis that cardiac-specific Gdf11 deficiency might lead to cardiac hypertrophy in young adulthood. We observed that targeted deletion of Gdf11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation when compared with control mice carrying only the Myh6-cre or Gdf11-floxed alleles, suggesting a possible etiology for dilated cardiomyopathy. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected model. First, whole heart Gdf11 expression did not decrease in Myh6-cre; Gdf11-floxed mice, possibly because of upregulation of Gdf11 in noncardiomyocytes in the heart. Second, we observed Cre-associated toxicity, with lower body weights and increased global fibrosis, in Cre-only control male mice compared with flox-only controls, making it challenging to infer which changes in Myh6-cre;Gdf11-floxed mice were the result of Cre toxicity versus deletion of Gdf11. Third, we observed differential expression of cre mRNA in Cre-only controls compared with the cardiomyocyte-specific knockout mice, also making comparison between these two groups difficult. Thus, targeted Gdf11 deletion in cardiomyocytes may lead to left ventricular dilation without hypertrophy, but alternative animal models are necessary to understand the mechanism for these findings. NEW & NOTEWORTHY We observed that targeted deletion of growth differentiation factor 11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation compared with control mice carrying only the Myh6-cre or growth differentiation factor 11-floxed alleles. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected mouse model.

Dataset Information

Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice.

Publications

Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice.

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