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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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Morphology and histology of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc.(A) Representative photographs of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc. (B) H&E staining of radial sections of placentas. sp, spongiotrophoblast layer; la, labyrinthine layer. Lower panels are the higher magnification of the upper panels. (C) Immunohistochemisty of radial sections of placentas with an antibody to PECAM, an angiogenesis marker. Middle panels are the higher magnification of the upper panels, and lower panels are the higher magnification of the middle panels.
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pone-0037070-g005: Morphology and histology of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc.(A) Representative photographs of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc. (B) H&E staining of radial sections of placentas. sp, spongiotrophoblast layer; la, labyrinthine layer. Lower panels are the higher magnification of the upper panels. (C) Immunohistochemisty of radial sections of placentas with an antibody to PECAM, an angiogenesis marker. Middle panels are the higher magnification of the upper panels, and lower panels are the higher magnification of the middle panels.

Mentions: To further delineate the mechanism underlying the growth retardation of Cul4b heterozygotes during prenatal development, we examined the morphology and histology of placentas at E14.5. Placentas of Cul4b heterozygous embryos appeared smaller and paler than those of wild-type (Fig. 5A). H&E staining of placental sections showed that the labyrinth layer of Cul4b heterozygous placentas was more loosely formed compared to that of wild-type controls, and was deeply invaded by the spongiotrophoblast layer, leaving the demarcation between labyrinth and spongiotrophoblast layers indiscernible (Fig. 5B, upper panels). While the network in the labyrinth layer of placentas in the wild-type was highly compacted and densely branched; the labyrinth layer in Cul4b heterozygotes was laid out very loosely (Fig. 5B, lower panels). The labyrinth and spongiotrophoblast layers were indistinguishable in the placentas of absorbed embryos.


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)

Morphology and histology of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc.(A) Representative photographs of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc. (B) H&E staining of radial sections of placentas. sp, spongiotrophoblast layer; la, labyrinthine layer. Lower panels are the higher magnification of the upper panels. (C) Immunohistochemisty of radial sections of placentas with an antibody to PECAM, an angiogenesis marker. Middle panels are the higher magnification of the upper panels, and lower panels are the higher magnification of the middle panels.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037070-g005: Morphology and histology of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc.(A) Representative photographs of placentas of wild-type, Cul4b heterozygous and absorbed embryos at 14.5 dpc. (B) H&E staining of radial sections of placentas. sp, spongiotrophoblast layer; la, labyrinthine layer. Lower panels are the higher magnification of the upper panels. (C) Immunohistochemisty of radial sections of placentas with an antibody to PECAM, an angiogenesis marker. Middle panels are the higher magnification of the upper panels, and lower panels are the higher magnification of the middle panels.
Mentions: To further delineate the mechanism underlying the growth retardation of Cul4b heterozygotes during prenatal development, we examined the morphology and histology of placentas at E14.5. Placentas of Cul4b heterozygous embryos appeared smaller and paler than those of wild-type (Fig. 5A). H&E staining of placental sections showed that the labyrinth layer of Cul4b heterozygous placentas was more loosely formed compared to that of wild-type controls, and was deeply invaded by the spongiotrophoblast layer, leaving the demarcation between labyrinth and spongiotrophoblast layers indiscernible (Fig. 5B, upper panels). While the network in the labyrinth layer of placentas in the wild-type was highly compacted and densely branched; the labyrinth layer in Cul4b heterozygotes was laid out very loosely (Fig. 5B, lower panels). The labyrinth and spongiotrophoblast layers were indistinguishable in the placentas of absorbed embryos.

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