title: Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.
abstract: Cullin-RING ligases (CRLs) complexes participate in the regulation of diverse cellular processes, including cell cycle progression, transcription, signal transduction and development. Serving as the scaffold protein, cullins are crucial for the assembly of ligase complexes, which recognize and target various substrates for proteosomal degradation. Mutations in human CUL4B, one of the eight members in cullin family, are one of the major causes of X-linked mental retardation. We here report the generation and characterization of Cul4b knockout mice, in which exons 3 to 5 were deleted. In contrast to the survival to adulthood of human hemizygous males with CUL4B null mutation, Cul4b null mouse embryos show severe developmental arrest and usually die before embryonic day 9.5 (E9.5). Accumulation of cyclin E, a CRL (CUL4B) substrate, was observed in Cul4b null embryos. Cul4b heterozygotes were recovered at a reduced ratio and exhibited a severe developmental delay. The placentas in Cul4b heterozygotes were disorganized and were impaired in vascularization, which may contribute to the developmental delay. As in human CUL4B heterozygotes, Cul4b null cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues. Together, our results showed that CUL4B is indispensable for embryonic development in the mouse.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zou
authors.forename: Chenhong
authors.initials: C
authors.lastname: Guo
authors.forename: Bingxi
authors.initials: B
authors.lastname: Chen
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D020964:Embryo Loss / Q000201:enzymology / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D005091:Exons; D005260:Female; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000196:embryology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000002:abnormalities / Q000098:blood supply / Q000201:enzymology; D011247:Pregnancy; D017384:Sequence Deletion; D013045:Species Specificity; D049951:X Chromosome Inactivation
chemical_list: C517832:CUL4B protein, human; C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D018076:DNA, Complementary