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Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.

Jiang B, Zhao W, Yuan J, Qian Y, Sun W, Zou Y, Guo C, Chen B, Shao C, Gong Y - PLoS ONE (2012)

Bottom Line: 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 cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.

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 mutation, Cul4b 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 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 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.

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Growth retardation of Cul4b heterozygous mice during embryonic development.(A) Bodyweights of Cul4b heterozygous mice and littermate wild-type females after birth. Data were presented as mean±SD. N = 8, *: p<0.05; **: p<0.01; ***: p<0.001. (B–E) Representative photographs of Cul4b heterozygous embryos and littermate wild-type controls at 9.5 (B), 10.5 (C), 12.5 (D) and 14.5 (E) dpc. The bar represents 1 mm in (B–C) and 2 mm in (D) and (E), respectively.
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pone-0037070-g004: Growth retardation of Cul4b heterozygous mice during embryonic development.(A) Bodyweights of Cul4b heterozygous mice and littermate wild-type females after birth. Data were presented as mean±SD. N = 8, *: p<0.05; **: p<0.01; ***: p<0.001. (B–E) Representative photographs of Cul4b heterozygous embryos and littermate wild-type controls at 9.5 (B), 10.5 (C), 12.5 (D) and 14.5 (E) dpc. The bar represents 1 mm in (B–C) and 2 mm in (D) and (E), respectively.

Mentions: While no Cul4b conceptuses could survive to E9.5, the Cul4b heterozygous females were also recovered at a lower than expected ratio at weaning (Table 1). This deficit was probably caused by an increased prenatal lethality in Cul4b heterozygotes, because their ratio was reduced even at E14.5. For the Cul4b heterozygotes that survive to term, they were significantly smaller than their wild-type littermates. The average body weight of heterozygous newborns (1.13±0.17 g) was much smaller than that of wild-type controls (1.79±0.12 g). However, Cul4b heterozygous mice were able to gradually catch up after birth, and the body weight difference became narrow in adults (Fig. 4A). Except for growth retardation, Cul4b heterozygous mice showed no gross abnormalities for the first 18 months.


Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.

Jiang B, Zhao W, Yuan J, Qian Y, Sun W, Zou Y, Guo C, Chen B, Shao C, Gong Y - PLoS ONE (2012)

Growth retardation of Cul4b heterozygous mice during embryonic development.(A) Bodyweights of Cul4b heterozygous mice and littermate wild-type females after birth. Data were presented as mean±SD. N = 8, *: p<0.05; **: p<0.01; ***: p<0.001. (B–E) Representative photographs of Cul4b heterozygous embryos and littermate wild-type controls at 9.5 (B), 10.5 (C), 12.5 (D) and 14.5 (E) dpc. The bar represents 1 mm in (B–C) and 2 mm in (D) and (E), respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351389&req=5

pone-0037070-g004: Growth retardation of Cul4b heterozygous mice during embryonic development.(A) Bodyweights of Cul4b heterozygous mice and littermate wild-type females after birth. Data were presented as mean±SD. N = 8, *: p<0.05; **: p<0.01; ***: p<0.001. (B–E) Representative photographs of Cul4b heterozygous embryos and littermate wild-type controls at 9.5 (B), 10.5 (C), 12.5 (D) and 14.5 (E) dpc. The bar represents 1 mm in (B–C) and 2 mm in (D) and (E), respectively.
Mentions: While no Cul4b conceptuses could survive to E9.5, the Cul4b heterozygous females were also recovered at a lower than expected ratio at weaning (Table 1). This deficit was probably caused by an increased prenatal lethality in Cul4b heterozygotes, because their ratio was reduced even at E14.5. For the Cul4b heterozygotes that survive to term, they were significantly smaller than their wild-type littermates. The average body weight of heterozygous newborns (1.13±0.17 g) was much smaller than that of wild-type controls (1.79±0.12 g). However, Cul4b heterozygous mice were able to gradually catch up after birth, and the body weight difference became narrow in adults (Fig. 4A). Except for growth retardation, Cul4b heterozygous mice showed no gross abnormalities for the first 18 months.

Bottom Line: 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 cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.

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 mutation, Cul4b 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 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 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.

Show MeSH
Related in: MedlinePlus