Molecular genetic analysis of therump white mutation in the mouse

The mouse rump white (Rw) mutation causes a pigmentation defect in heterozygotes and embryonic lethality in homozygotes (Searle and Truslove, 1970). At E7.5, Rw/Rw embryos are retarded in growth, fail to complete neurulation, and die around E9.5 (Bucan et al., 1995). Rw is closely linked to the mutations patch (Ph) and dominant spotting (W) in the central portion of mouse chromosome 5 and is associated with a 30 cM chromosomal inversion (Nagle et al., 1994; Stephenson et al., 1994). The distal breakpoint of the Rw inversion was cloned in a chromosomal walk in the Kit-Pdgfra intergenic region, towards Kit. The Rw distal inversion breakpoint is located 160 kb to 220 kb proximal to Kit and has tissue-specific effects on Kit expression during embryogenesis. Kit misexpression may be responsible for the dominant pigmentation defect in Rw/+ mice. Rw/Rw embryonic lethality is complemented by the W19H deletion, which spans the distal boundary of the Rw inversion, suggesting that the Rw lethality is not caused by a gene at the distal end of the inversion (Lyon et al., 1984; Nagle et al., 1994). A genomic probe D5Buc4 which contains the distal breakpoint of the Rw inversion was used to isolate a cosmid containing the proximal breakpoint of Rw from a genomic library of Rw/+. Nucleotide sequence analysis of 29 kb flanking the breakpoint identified four exons corresponding to the gene encoding dipeptidyl aminopeptidase-like protein 6 (Dpp6) (Wada et al., 1992; de Lecea et al., 1994). The DPP6 protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain, and a long C-terminal extracellular domain (Wada et al., 1992; Yokotani et al., 1993), and the recessive lethality of Rw is probably due to the disruption of Dpp6 (Wada et al., 1992), located at the proximal inversion breakpoint. An embryonic transcript of Dpp6 is expressed in wild-type embryos at early post-implantation stages, suggesting that Dpp6 may have a novel function in embryonic development