Recent advances in the molecular and genetic analysis of mouse development have made it possible to address the molecular basis of processes involved in pattern formation

Recent advances in the molecular and genetic analysis of mouse development have made it possible to address the molecular basis of processes involved in pattern formation and morphogenesis (for reviews see Rossant and Joyner, 1989; Gridley, 1991; Gossler and Balling, 1992; Rossant and Hopkins, 1992). This has been illustrated by the recent characterization of mouse mutants, which has led to the identification of several important genes (Epstein et al., 1991; Hill et al., 1991; Suter et al., 1992; Thomas et al., 1991; for review see Reith and Bernstein, 1991). In this context, the developing limb has attracted much attention as a model system since many mutations exist affecting its proper development. Among them the mutant extra-toes (Xt) has been described as a member of a group of mutant loci affecting the limb skeletal pattern (Hinchcliffe and Johnson, 1980). The phenotype of Xt mice is characterized by the formation of extra digits (polydactyly) on the preaxial (anterior) site of the limb (Johnson, 1967). This polydactyly is possibly the result of an enlarged apical ectodermal ridge (AER), which presumably induces some of the underlying mesenchyme to form additional skeletal elements. In homozygous Xt/Xt mice, more proximal parts of the limb skeleton are also affected. Animals die in utero, or at birth, with a range of abnormalities including malformations of the brain, central nervous system and sense organs. As a result of morphological studies and comparative gene mapping studies, Xt has been proposed to be an animal model for the human Greig Cephalopolysyndactyly Syn drome (GCPS) (Winter and Huson, 1988), an autosomal mutation affecting limb and craniofacial development (Greig, 1926). Recently the zinc finger gene GLI3 has been proposed as a candidate gene for GCPS since it was shown to be interrupted by translocations in Greig syndrome families (Vortkamp et al., 1991). GLI3 has been isolated and described as a member of a gene family that is related to the Drosophila gap gene Krüppel (Ruppert et al., 1988, 1990). This family has been proposed to play a role in embryonic development and tissue-specific differentiation (Ruppert et al., 1988). We describe the analysis of Gli3 gene expression in wildtype and mutant Xt mice and during normal development. Our results strongly support the suggestion that interference with Gli3 gene function during embryogenesis results in the Xt phenotype.