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Mice lacking DCAF2 in placenta die at the gastrulation stage

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Abstract

UV-damaged DNA-binding protein 1 (DDB1) and cullin 4-associated factor 2 (DCAF2, also known as DTL or CDT2) is an evolutionarily highly conserved substrate recognition factor in the cullin 4 RING E3 ubiquitin ligase (CRL4) complex. This complex degrades multiple DNA replication and cell cycle-associated proteins to maintain genome stability. To clarify the function of DCAF2 in vivo, we used Cre recombinase driven by the Elf5 promoter to generate knockout mouse model that was specifically deleted Dcaf2 in the trophoblast lineage (Elf5-Cre; Dcaf2fl/fl, Dcaf2 cKO). Here, we show that mice with the genotype Elf5-Cre; Dcaf2fl/+ are normal and fertile. However, after mating of Elf5-Cre; Dcaf2fl/+ mice with Dcaf2fl/fl, no Dcaf2 cKO pups were born. Timed pregnancy studies have shown that Dcaf2 cKO mice developed abnormally on embryonic day 5.5 and died at gastrulation stage. It is worth noting that the extraembryonic ectoderm of Dcaf2 cKO mice is severely reduced or missing and leading to embryonic death. We also proved that stronger DNA damage accumulated in the trophoblastic cells of Dcaf2 cKO mice at E8.5. In addition, higher expression of Caspase-3 was found in the embryonic and trophoblastic cells of these cKO mice. In general, our research shows that the placental DCAF2 is crucial to the formation of gastrula.

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Acknowledgements

The authors gratefully thank Prof. Haibin Wang and Dr. Shuangbo Kong for providing Elf5-Cre mouse for us.

Funding

This study was supported by the National Key R&D Program of China (2019YFA0802600) and the National Natural Science Foundation of China (32170863, 31871512). Support was also obtained from the Shanghai Commission of Science and Technology (17DZ2271100) and Open Project of Shandong Provincial Key Laboratory of Reproductive Medicine (SDKL2017018).

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Authors and Affiliations

  1. Key Laboratory of Animal Resistance Research, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Science, Shandong Normal University, No.88 East Wenhua Road, Jinan, 250014, Shandong, China

    Man Yang, Zongting Wang & Cong Zhang

  2. Department of Obstetrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, Shandong, China

    Mei Liu

  3. Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China

    Cong Zhang

  4. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China

    Cong Zhang

  5. Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, 250001, Shandong, China

    Cong Zhang

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  1. Man Yang
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  2. Mei Liu
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  3. Zongting Wang
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  4. Cong Zhang
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Contributions

CZ and MY conceived and designed the study. MY performed the experiments and drafted the manuscript. ML acquired data. ZTW analyzed and interpreted data. CZ and MY revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Cong Zhang.

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Yang, M., Liu, M., Wang, Z. et al. Mice lacking DCAF2 in placenta die at the gastrulation stage. Cell Tissue Res 389, 559–572 (2022). https://doi.org/10.1007/s00441-022-03655-4

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