DOUBLEFOOT - A NEW MOUSE MUTANT AFFECTING DEVELOPMENT OF LIMBS AND HEAD

The mutant doublefoot, Dbf, of the mouse arose spontaneously, and was shown to be inherited as an autosomal dominant, mapping 9-13 cM proxim al to leaden, In, on chromosome 1 and showing no recombination with th e microsatellite markers D1Mit24 and D1Mit77. In heterozygotes the phe notype includes many extra toes on all four feet, and the tibia and fi bula may be reduced and bowed. The head is shortened and broad and the eyes are held half-closed, and some animals develop hydrocephalus. Th e tail is kinked and abnormally thick, and the soles of the feet are s wollen. Growth is retarded, viability is reduced, and reproduction is impaired in both sexes. Only about 30% of males are normally fertile, and testis weights and sperm counts may be reduced, although this appe ars not to be the main cause of poor fertility. In females vaginal ope ning is delayed and oestrous cycles are irregular, although the animal s appear to respond to gonadotrophic hormones. Crosses of Dbf/+ x Dbf/ + are very poorly fertile. Prenatally, Dbf/+ heterozygotes can first b e recognized at 11 1/2 days gestation by abnormally broad fore limb bu ds. Putative Dbf/Dbf homozygotes at 12 1/2 days have similar limbs def ects and also split face, due to failure of the maxillae to fuse in th e midline. Some homozygotes and a few putative heterozygotes have cran ioschisis. At 13 1/2 days, the heads of homozygotes tend to bulge in t he frontal region and a bleb of clear fluid is visible medially. At 14 1/2 days Dbf/Dbf fetuses may have oedema and some are dead. From 15 1 /2 days onwards no live Dbf/Dbf fetuses have been found. The gene maps close to the locus of Pax3, but crossovers between Dbf and Pax3 have been found, ruling out the possibility that a gain-of-function mutatio n in Pax3 might be involved.