title: Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis.
abstract: 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 p21(Cip1/WAF) and G2/M cell cycle arrest, which could be partially rescued by silencing of p21(Cip1/WAF). Epiblast-specific 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-deficient mice to model the potential neuronal and behavioral deficiencies of human CUL4B XLMR patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA.
authors.forename: Liren
authors.initials: L
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.forename: Yuewei
authors.initials: Y
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: Prevedel
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Lacy
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D003433:Crosses, Genetic; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D020964:Embryo Loss / Q000201:enzymology / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D047108:Embryonic Development; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D005838:Genotype; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D040582:Inheritance Patterns; D059566:M Phase Cell Cycle Checkpoints; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011247:Pregnancy; D049951:X Chromosome Inactivation
chemical_list: C493957:Cdkn1a protein, mouse; C524851:Cul4B protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21