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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

This work was supported in part by Public Health Service grant RO1 CA093804 from the National Cancer Institute. T.T. was supported in part by the Toyobo Biotechnology Foundation.

We thank Roderick Bronson and Gerald Chu at the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core, William Lane at the Harvard Microchemistry and Proteomics Analysis Facility, and Edward Fox at the Dana-Farber Microarray Core Facility. The ES cell line was obtained from the National Heart, Lung, and Blood Institute-funded Program for Genomic Applications at BayGenomics. We thank Elizabeth Bland and Peter Scambler for identifying the CUL7 mutation in the 3-M syndrome patient cell line.