title: CUL-4A is critical for early embryonic development.
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.
authors.affiliation: Department of Pediatric, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut Street, Indianapolis, IN 46202, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Li
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Ruiz
authors.forename: Kristin T
authors.initials: KT
authors.lastname: Chun
mesh_terms: D000818:Animals; D001483:Base Sequence; D001755:Blastocyst / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics; D044842:Cullin Proteins; D004247:DNA / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005865:Gestational Age; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy
chemical_list: C114234:CUL4A protein, human; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D009363:Neoplasm Proteins; D004247:DNA