An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina

The Acrg minimal region is a 1.5-1.7Mb domain defined by genetic complementation among deletions generated around Ednrb on chromosome 14 in mice. Mice homozygous for one of the deletions, Ednrb^s-1Acrg, exhibit embryonic lethality with defects associated with mesoderm development. We predicted that the region contains a single cluster of four genes that encode a TBC domain-containing protein (KIAA0603), a novel protein AK000009, the ubiquitin C-terminal hydrolase L3 (UCHL3) and an F-box/PDZ/LIM domain protein LMO7. A targeted internal deletion of Uchl3 (Uchl3^Δ3-7) produced viable mice, eliminating this gene as a candidate for the embryonic lethality. To dissect the Acrg minimal region further, we utilized Cre-loxP-mediated chromosome engineering to generate a targeted 800 kb deletion (Lmo7^Δ800) that removes the distal portion of the region. The deletion includes Uchl3, Lmo7 and an additional 500 kb downstream of the 3′ end of Lmo7 where no genes are thought to reside. We found that ∼40% of mice homozygous for this deletion die between birth and weaning, and are severely runted. The remaining homozygotes are viable, thus ruling out Lmo7 as a single gene candidate for the Ednrb^s-1Acrg embryonic lethality. Both Uchl3^Δ3-7 and Lmo7^Δ800 mutants displayed retinal degeneration, muscular degeneration and growth retardation, but the severity of the muscular degeneration and growth retardation were enhanced in Lmo7^Δ800 homozygotes. We suggest that the increase in severity may reflect an interaction between Uchl3 and Lmo7 in the ubiquitin-mediated protein degradation pathway.