Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development

Cullin-based ubiquitin ligases (E3s) constitute one of the largest E3 families. Fbxw8 (also known as Fbw6 or Fbx29) is an F-box protein that is assembled with Cul7 in an SCF-like E3 complex. Here we show that Cu17 forms a heterodimeric complex with Cull in a manner dependent on Fbxw8. We generated mice deficient in Fbxw8 and found that Cu17 did not associate with Cull in cells of these mice. Two-thirds of Fbxw8(-/-) embryos die in utero, whereas the remaining one-third are born alive and grow to adulthood. Fbxw8(-/-) embryos show intrauterine growth retardation and abnormal development of the placenta, characterized by both a reduced thickness of the spongiotrophoblast layer and abnormal vessel structure in the labyrinth layer. Although the placental phenotype of Fbxw8(-/-) mice resembles that of Cul7(-/-) mice, other abnormalities of Cul7(-/-) mice are not apparent in Fbxw8(-/-) mice. These results suggest that the Cul7-based SCF-like E3 complex has both Fbxw8-dependent and Fbxw8-independent functions.