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The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries

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Abstract

Pudgy (pu) homozygous mice exhibit clear patterning defects at the earliest stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities1. By positional cloning and complementation, we have determined that the pu phenotype is caused by a mutation in the delta-like 3 gene (Dll3), which is homologous to the Notch-ligand Delta in Drosophila. Histological and molecular marker analyses show that the pu mutation disrupts the proper formation of morphological borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicates an important role in early development. The results point to a key role for a Notch -signalling pathway in the initiation of patterning of vertebrate paraxial mesoderm.

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Figure 1: Positional cloning and complementation of the pu locus.
Figure 2: Alternatively spliced Dll3 and the pu mutant allele.
Figure 3: Somite defects in the pu mutant.
Figure 4: Postnatal phenotypes of the pu mutation, with the wild-type heterozygous phenotype on the left, and the mutant on the right.

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Acknowledgements

We thank K. Devon, C. Dunbar, M. Nguyen, J. Reis, M. Velez-Stringer, D. Wilcomb and J. Williams for invaluable technical assistance; and P. Bain, L. Bradley, M. Daly, J. Dausmann, W. Dietrich, L. Gammill, H. Gardner, A. Gossler, B. Hamilton, J. Hästbacka, T. Hawkins, H. Jacob, P. Kolm, J. Lanni, F. Lewitter, P. Kolm, A. MacMurray, J. Nemhauser, A. Pettersson, M.P. Reeve, C. Rosenberg, J. Segrè and A. Sidow for technical advice. Key reagents were provided by R. Beddington, S. Dunwoodie, A. Gossler, M. Haldi, B. Hogan, R. Johnson, C. Kozak and A. MacMahon. We thank L. Bradley, D. Fambrough and A. Sidow for comments on the manuscript, and R. Johnson and T. Gridley for helpful discussions. This work was supported in part by NIH grants (E.S.L, B.L.B., R.T.B. and W.N.F.) and a Klingenstein Fellowship (W.N.F.).

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  1. Kenro Kusumi

    Present address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

Authors and Affiliations

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

    Kenro Kusumi, Eileen Sun, Anne W. Kerrebrock, Dow-Chung Chi, Monique Bulotsky, Jessica B. Spencer, Bruce W. Birren & Eric S. Lander

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Kenro Kusumi, Dow-Chung Chi & Eric S. Lander

  3. Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, 02111, Massachusetts, USA

    Roderick T. Bronson

  4. The Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Wayne N. Frankel

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  1. Kenro Kusumi
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Correspondence to Kenro Kusumi or Eric S. Lander.

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Kusumi, K., Sun, E., Kerrebrock, A. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nat Genet 19, 274–278 (1998). https://doi.org/10.1038/961

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