A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant

Early outgrowth of the vertebrate embryonic limb requires signalling by the apical ectodermal ridge (AER) to the progress zone (PZ), which in response proliferates and lays down the pattern of the presumptive limb in a proxim al to distal progression(1). Signals from the PZ maintain the AER until the anlagen for the distal phalanges have been formed(2). The semidominant mou se mutant dactylaplasia (Dac) disrupts the maintenance of the AER, leading to truncation of distal structures of the developing footplate, or autopod( 3-5). Adult Dac homozygotes thus lack hands and feet except for malformed s ingle digits, whereas heterozygotes lack phalanges of the three middle digi ts. Dac resembles the human autosomal dominant split hand/foot malformation (SHFM) diseases. One of these, SHFM3, maps to chromosome 10q24 (refs 6,7), which is syntenic to the Dac region on chromosome 19, and may disrupt the orthologue of Dac. We report here the positional cloning of Dac and show th at it belongs to the F-box/WD40 gene family, which encodes adapters that ta rget specific proteins for destruction by presenting them to the ubiquitina tion machinery(8). In conjuction with recent biochemical studies(9-12), thi s report demonstrates the importance of this gene family in vertebrate embr yonic development.