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Mice lacking DCAF2 in placenta die at the gastrulation stage
Man Yang1, Mei Liu2, Zongting Wang1
1Key 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.
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.
Insights
Mice lacking placental DCAF2 (DNA damage-binding protein 1 and cullin 4-associated factor 2) die during early development. This highlights DCAF2
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- UV-damaged DNA-binding protein 1 (DDB1) and cullin 4-associated factor 2 (DCAF2) is a key component of the CRL4 E3 ubiquitin ligase complex.
- This complex regulates DNA replication and cell cycle progression, maintaining genome stability.
- Understanding DCAF2's in vivo function is crucial for comprehending its role in development.
Purpose of the Study:
- To investigate the in vivo function of DCAF2 in the mouse trophoblast lineage.
- To determine the developmental consequences of DCAF2 deletion in this specific cell type.
Main Methods:
- Generation of a conditional knockout mouse model (Elf5-Cre; Dcaf2fl/fl) to specifically delete Dcaf2 in the trophoblast.
- Timed pregnancy studies to observe embryonic development and viability.
- Analysis of DNA damage accumulation and apoptosis (Caspase-3 expression) in Dcaf2-deficient embryos.
Main Results:
- Conditional knockout of Dcaf2 in the trophoblast lineage (Dcaf2 cKO) resulted in embryonic lethality by the gastrulation stage (embryonic day 5.5).
- Dcaf2 cKO embryos exhibited severe reduction or absence of the extraembryonic ectoderm.
- Increased DNA damage and elevated Caspase-3 expression were observed in trophoblastic cells of Dcaf2 cKO embryos.
Conclusions:
- Placental DCAF2 is essential for proper embryonic development, particularly for gastrulation.
- DCAF2 plays a critical role in maintaining genome stability and preventing apoptosis within the trophoblast.
- The absence of DCAF2 leads to developmental defects and embryonic death due to compromised trophoblast function.
