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Molecular and Cellular Biology, July 2002, p. 4997-5005, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.4997-5005.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

CUL-4A Is Critical for Early Embryonic Development

Binghui Li,1,2 Joseph C. Ruiz,1 and Kristin T. Chun1,2*

Department of Pediatrics,1 Department of Biochemistry and Molecular Biology, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 462022

Received 23 January 2002/ Returned for modification 15 March 2002/ Accepted 17 April 2002

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.

* Corresponding author. Mailing address: Herman B Wells Center for Pediatric Research, Cancer Research Building, Rm. 474, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202. Phone: (317) 278-2824. Fax: (317) 274-8679. E-mail: kchun{at}iupui.edu.

Molecular and Cellular Biology, July 2002, p. 4997-5005, Vol. 22, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.14.4997-5005.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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