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Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.

ABSTRACT: CUL7 binds to SKP1, RBX1, and FBXW8 to form a cullin-RING ligase, or an SKP1-cullin-F box protein complex. The targeted disruption of the Cul7 gene in mice results in significant reduction in embryo size and neonatal lethality. In humans, CUL7 was found to be mutated in the 3-M dwarfism syndrome characterized by severe pre- and postnatal growth retardation, indicating that CUL7 is closely associated with human and mouse growth. We generated mice lacking Fbxw8 by gene trapping. Similar to Cul7(-/-) animals, Fbxw8(-/-) embryos and placentas were smaller than wild-type and heterozygous littermates and placentas. Approximately 30% of the expected number of Fbxw8(-/-) mice survived birth, but these mice remained smaller than their wild-type and heterozygous littermates throughout postnatal development. FBXW8 expression was detected in most organs of wild-type mice examined, and the organs in Fbxw8(-/-) mice were smaller than those in wild-type mice. Fbxw8 expression levels were highest in skeletal muscle, cartilage, and lung tissue. Expression profiling revealed elevated levels of insulin-like growth factor binding protein 1 (IGFBP1) transcripts in Fbxw8(-/-) embryos. Furthermore, we observed increased levels of IGFBP2 in Cul7(-/-) as well as Fbxw8(-/-) fibroblasts. These results demonstrate that the FBXW8-CUL7 complex plays a significant role in growth control.

SUBMITTER: Tsutsumi T

PROVIDER: S-EPMC2223430 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.

Tsutsumi Takeya T Kuwabara Hiroshi H Arai Takehiro T Xiao Yonghong Y Decaprio James A JA

Molecular and cellular biology 20071112 2

CUL7 binds to SKP1, RBX1, and FBXW8 to form a cullin-RING ligase, or an SKP1-cullin-F box protein complex. The targeted disruption of the Cul7 gene in mice results in significant reduction in embryo size and neonatal lethality. In humans, CUL7 was found to be mutated in the 3-M dwarfism syndrome characterized by severe pre- and postnatal growth retardation, indicating that CUL7 is closely associated with human and mouse growth. We generated mice lacking Fbxw8 by gene trapping. Similar to Cul7(-/ ...[more]

PMID: 17998335

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Project description:A number of studies have reported the occurrence of long-term metabolic disorders in mammals following intrauterine growth retardation (IUGR). However, the effects of dietary patterns during IUGR have not been fully elucidated. The present study aimed to evaluate the effects of different dietary patterns during critical growth windows on metabolic outcomes in the offspring of rats with IUGR. Male offspring rats from mothers fed either a normal or low-protein diet were randomly assigned to one of the following groups: Normal diet throughout pregnancy, lactation and after weaning (CON); normal diet throughout pregnancy and high-fat diet throughout lactation and after weaning (N + H + H); low-protein diet throughout pregnancy and high-fat diet throughout lactation and after weaning (IUGR + H + H); low-protein diet throughout pregnancy and lactation and high-fat diet after weaning (IUGR + L + H); and low-protein diet throughout pregnancy and normal diet throughout lactation and after weaning. During lactation, the male offspring in the N + H + H group exhibited the fastest growth rate, whereas the slowest rate was in the IUGR + L + H group. Following weaning, all IUGR groups demonstrated significant catch-up growth. Abnormal insulin tolerance were observed in the N + H + H, IUGR + H + H and IUGR + L + H groups and insulin sensitivity was decreased in IUGR + L + H group. The triglycerides/high-density lipoprotein ratio in the IUGR + L + H group was significantly higher compared with in the other groups. The abdominal circumference, Lee's index and adipocyte diameter of IUGR groups were significantly increased compared with the CON group. High levels of leptin and interleukin-6 in adipose tissues, and low adiponectin were observed in the IUGR + L + H group. Different dietary patterns during specific growth windows showed numerous impacts on glycolipid metabolism in IUGR offspring. The present study elucidated the mechanisms and potential options for IUGR treatment and prevention.

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Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.

Publications

Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.

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