The FBXW8 protein is a component of cullin-RING ligase (SKP1-cullin-F box protein complex) that is part of the ubiquitin-proteasome pathway of protein degradation. These mice carry a mutation of the Fbxw8, F-box and WD-40 domain protein 8, gene. Heterozygous mice are viable and fertile. Homozygous mice have a perinatal lethal phenotype with 70% dying soon after birth. Homozygous embryos are viable until late gestation. Gene product (protein) is almost undetectable by Western blot analysis of MEFs from homozygotes. Low levels of gene product (mRNA), 0.8% of levels seen in wildtype controls, are detected in MEFs isolated from homozygotes, as analyzed by real time PCR. At E12.5, homozygotes are smaller in size than controls, and become progressively smaller. By E18.5, the size reduction of homozygous embryos and placentas is significant, 67% of littermate size and 60 to 67% of wildtype placenta size, respectively. Homozygous embryos, aged E18.5, display impaired respiration and quickly become cyanotic. Histological analysis of lungs from homozygous E18.5 embryos reveals diminished alveolar space. Mutant mice exhibit a thin and disorganized placental spongiotrophoblast layer. Homozygotes that survive postnatally are smaller in size than wildtype littermates and exhibit a slower growth rate. Homozygotes, aged 3 months, exhibit smaller organ weight for liver, spleen, kidney, lungs and heart, but have brains similar in size to wildtype mice. Strong β-galactosidase expression is detected in skeletal muscle, developing bone epiphyses, bronchial epithelia of homozygous E14.5 and E18.5 embryos. Weaker β-galactosidase expression is detected in smooth muscle, kidneys, eyes, skin, and brain. β-galactosidase expression is also detected in the placenta. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6 genetic background.