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Cul4b is essential for mouse embryonic development 1258
Cell Research (2012) 22:1258-1269. 2012 IBCB, SIBS, CAS All rights reserved 1001-0602/12 $ 32.00
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ORIGINAL ARTICLE
www.nature.com/cr
Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis
Liren Liu1, Yan Yin2, Yuewei Li1, Lisa Prevedel1, Elizabeth H Lacy3, Liang Ma2, Pengbo Zhou1
1Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA; 2Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110, USA; 3Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Mutations of the CUL4B ubiquitin ligase gene are causally linked to syndromic X-linked mental retardation (XLMR). However, the pathogenic role of CUL4B mutations in neuronal and developmental defects is not understood. We have generated mice with targeted disruption of Cul4b, and observed embryonic lethality with pronounced growth inhibition and increased apoptosis in extra-embryonic tissues. Cul4b, but not its paralog Cul4a, is expressed at high levels in extra-embryonic tissues post implantation. Silencing of CUL4B expression in an extra-embryonic cell line resulted in the robust accumulation of the CUL4 substrate p21Cip1/WAF and G2/M cell cycle arrest, which could be partially rescued by silencing of p21Cip1/WAF. Epiblast-specic deletion of Cul4b prevented embryonic lethality and gave rise to viable Cul4b null mice. Therefore, while dispensable in the embryo proper, Cul4b performs an essential developmental role in the extra-embryonic tissues. Our study offers a strategy to generate viable Cul4b-decient mice to model the potential neuronal and behavioral deciencies of human CUL4B XLMR patients.
Keywords: cullin 4B; knockout; extra-embryonic tissue; ubiquitin; X-inactivationCell Research (2012) 22:1258-1269. doi:10.1038/cr.2012.48; published online 27 March 2012
Introduction
Mental retardation (MR) is a disability characterized by limitations of intellectual and adaptive skills. To date, over 900 genetic mutations are linked to MR, highlighting the enormous heterogeneity of this clinical condition [1]. Of the known genetic lesions, the X-chromosome harbors over 100 MR genes, far more than those found on autosomes. Recently, multiple mutations of the human CUL4B ubiquitin ligase gene (Xq24) were identied as being causally associated with X-linked MR (XLMR) [2-5]. CUL4B-deficient patients display clinical symptoms that include growth retardation, macrocephaly, hypogonadism, obesity, and ataxia [2-5].
CUL4B is a member...