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

Nature Genetics volume 23, pages 104–107 (1999)Cite this article

Abstract

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 proximal to distal progression1. Signals from the PZ maintain the AER until the anlagen for the distal phalanges have been formed2. The semidominant mouse mutant dactylaplasia (Dac) disrupts the maintenance of the AER, leading to truncation of distal structures of the developing footplate, or autopod3,4,5. Adult Dac homozygotes thus lack hands and feet except for malformed single digits, whereas heterozygotes lack phalanges of the three middle digits. 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 that it belongs to the F-box/WD40 gene family, which encodes adapters that target specific proteins for destruction by presenting them to the ubiquitination machinery8. In conjuction with recent biochemical studies9,10,11,12, this report demonstrates the importance of this gene family in vertebrate embryonic development.

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Figure 1: The Dac phenotype in the embryonic limb.
Figure 2: Genetic, physical and transcript map of the Dac region.
Figure 3: Characterization of the Dac mutations by blotting and sequencing.
Figure 4: Predicted sequence and function of dactylin.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank J. Dausman and R. Curry for help with mice; Z. Husain, K. Harris, K. Devon, K. Dewar, J. Rioux, T. Green, A. Kirby and C. Nusbaum for help with YACs, BACs and sequencing; K. Kusumi, M. Hosobuchi, J. Segre, B. Hamilton, D. Fambrough, A. Bortvin and members of the Jaenisch laboratory for discussions; and H. Sweet and P. Lane for expert assistance in initial characterization and linkage crosses of Dac1J and Dac2J mice.

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Authors and Affiliations

  1. Departments of Pathology and Genetics, SUMC R248B, Stanford, 94305-5324, California, USA

    Arend Sidow

  2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Monique S. Bulotsky, Anne W. Kerrebrock, Bruce W. Birren, David Altshuler, Rudolf Jaenisch & Eric S. Lander

  3. Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    Kenneth R. Johnson

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Correspondence to Arend Sidow or Eric S. Lander.

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Sidow, A., Bulotsky, M., Kerrebrock, A. et al. A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant. Nat Genet 23, 104–107 (1999). https://doi.org/10.1038/12709

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