PMID:12077329

Citation	Li, B, Ruiz, JC and Chun, KT (2002) CUL-4A is critical for early embryonic development. Mol. Cell. Biol. 22:4997-5005
Abstract	Ubiquitin-mediated degradation targets cell cycle regulators for proteolysis. Much of the ubiquitin pathway's substrate specificity is conferred by E3 ubiquitin ligases, and cullins are core components of some E3s. CUL-4A encodes one of six mammalian cullins and is amplified and/or overexpressed in breast cancer, which suggests a role in regulating cell cycle progression. To examine CUL-4A's physiologic function, we generated a CUL-4A deletion mutation in mice. No viable CUL-4A(-/-) pups and no homozygous mutant embryos as early as 7.5 days postcoitum (dpc) were recovered. However, CUL-4A(-/-) blastocysts are viable, hatch, form an inner cell mass and trophectoderm, and implant (roughly 4.5 dpc), indicating that CUL-4A(-/-) embryos die between 4.5 and 7.5 dpc. Despite 87% similarity between the Cul-4A and Cul-4B cullins, the CUL-4A(-/-) lethal phenotype indicates that CUL-4A has one or more distinct function(s). Surprisingly, 44% fewer heterozygous pups were recovered than expected by Mendelian genetics, indicating that many heterozygous embryos also die during gestation due to haploinsufficiency. Taken together, our findings indicate that appropriate CUL-4A expression is critical for early embryonic development.
Links	PubMed PMC139768
Keywords	Animals; Base Sequence; Blastocyst/cytology; Breast Neoplasms/genetics; Cullin Proteins; DNA/genetics; Embryonic and Fetal Development/genetics; Embryonic and Fetal Development/physiology; Female; Fetal Death/genetics; Gene Expression Regulation, Developmental; Gene Targeting; Gestational Age; Heterozygote; Homozygote; Humans; Mice; Mice, Knockout; Neoplasm Proteins/deficiency; Neoplasm Proteins/genetics; Neoplasm Proteins/physiology; Pregnancy
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:CUL4A	involved_in	GO:0001701: in utero embryonic development	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:CUL4A		GO:0001701: in utero embryonic development	ECO:0000315:		P		Table 1: In the group of offspring produced from heterozygous CUL4A mutant crosses, no homozygous CUL4A mutants were viable past the blastocyte stage. There were also significanly fewer heterozygote pups than expected based on mendialian genetics. This shows that CUL4A plays an important role in embryo development.	complete CACAO 9884

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