SERRATE2 IS DISRUPTED IN THE MOUSE LIMB-DEVELOPMENT MUTANT SYNDACTYLISM

The mouse syndactylism (sin) mutation impairs some of the earliest asp ects of limb development and leads to subsequent abnormalities in digi t formation(1-3). In sin homozygotes, the apical ectodermal ridge (AER ) is hyperplastic by embryonic day 10.5, leading to abnormal dorsovent ral thickening of the limb bud, subsequent merging of the skeletal con densations that give rise to cartilage and bone in the digits, and eve ntual fusion of digits. The AER hyperplasia and its effect on early di gital patterning distinguish sm from many other syndactylies that resu lt from later failure of cell death in the interdigital areas(4,5). He re we use positional cloning to show that the gene mutated in sm mice encodes the putative Notch ligand Serrate2. The results provide direct evidence that a Notch signalling pathway is involved in the earliest stages of Limb-bud patterning and support the idea that an ancient gen etic mechanism underlies both AER formation in vertebrates and wing-ma rgin formation in files(6,7). In addition to cloning the sm gene, we h ave mapped three modifiers of sm, for which we suggest possible candid ate genes.