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Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum mice

Nature volume 389, pages 963–966 (1997)Cite this article

Abstract

The development of characteristic visceral asymmetries along the left–right (LR) axis in an initially bilaterally symmetrical embryo is an essential feature of vertebrate patterning. The allelic mouse mutations inversus viscerum (iv)1,2 and legless (lgl)3,4 produce LR inversion, or situs inversus, in half of live-born homozygotes. This suggests that the iv gene product drives correct LR determination, and in its absence this process is randomized2. These mutations provide tools for studying the development of LR-handed asymmetry and provide mouse models of human lateralization defects. At the molecular level, the normally LR asymmetric expression patterns of nodal5 and lefty6 are randomized in iv/iv embryos, suggesting that iv functions early in the genetic hierarchy of LRspecification. Here we report the positional cloning of an axonemal dynein heavy-chain gene, left/right-dynein (lrd), that is mutated in both lgl and iv. lrd is expressed in the node of the embryo at embryonic day 7.5, consistent with its having a role in LR development7. Our findings indicate that dynein, a microtubule-based motor, is involved in the determination of LR-handed asymmetry and provide insight into the early molecular mechanisms of this process.

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Figure 1: Identification of a dynein gene deleted in lgl.
Figure 2: iv has a missense mutation in a highly conserved amino acid of Lrd.
Figure 3: RT-PCR analysis of embryonic and adult expression.
Figure 4: Expression of lrd localized by in situ hybridization.

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References

  1. Hummel, K. P. & Chapman, D. B. Visceral inversion and associated anomalies in the mouse. J. Hered. 50, 9– 13 (1959).

    Article  Google Scholar 

  2. Layton, W. M. Random determination of a developmental process. J. Hered. 67, 336–338 (1976).

    Article  Google Scholar 

  3. McNeish, J. D. et al. Phenotypic characterization of the transgenic mouse insertional mutation Legless. J. Exp. Zool. 253, 151–162 (1990).

    Article  CAS  Google Scholar 

  4. Singh, G. et al. legless insertional mutation: morphological, molecular, and genetic characterization. Genes Dev. 5, 2245–2255 (1991).

    Article  CAS  Google Scholar 

  5. Lowe, L. A. et al. Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381, 158–161 (1996).

    Article  ADS  CAS  Google Scholar 

  6. Meno, C. et al. Left–right asymmetric expression of the TGFβ-family member lefty in mouse embryos. Nature 381, 151–155 (1996).

    Article  ADS  CAS  Google Scholar 

  7. Lohr, J. L., Danos, M. C. & Yost, H. J. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124, 1465– 1472 (1997).

    CAS  PubMed  Google Scholar 

  8. Afzelius, B. A. Ahuman syndrome caused by immotile cilia. Science 193 , 317–319 (1976).

    Article  ADS  CAS  Google Scholar 

  9. Afzelius, B. A. Situs inversus and ciliary abnormalities: What is the connection? Int. J. Dev. Biol. 39, 839–844 (1995).

    CAS  PubMed  Google Scholar 

  10. Holzbaur, E. L. F. & Vallee, R. B. Dyneins: molecular structure and cellular function. Annu. Rev. Cell Biol. 10, 339–372 (1994).

    Article  CAS  Google Scholar 

  11. Asai, D. J. Multi-dynein hypothesis. Cell Motil. Cytoskel. 32, 129–132 (1995).

    Article  CAS  Google Scholar 

  12. Tanaka, Y., Zhang, Z. & Hirokawa, N. Identification and molecular evolution of new dynein-like protein sequences in rat brain. J. Cell Sci. 108, 1883–1893 (1995).

    CAS  PubMed  Google Scholar 

  13. Vaughan, K. T. et al. Multiple mouse chromosomal loci for dynein-based motility. Genomics 36, 29–38 (1996).

    Article  CAS  Google Scholar 

  14. Andrews, K. L., Nettesheim, P., Asai, D. J. & Ostrowski, L. E. Identification of seven rat axonemal dynein heavy chain genes: expression during ciliated cell differentiation. Mol. Biol. Cell 7, 71–79 (1996).

    Article  CAS  Google Scholar 

  15. McGrath, J., Horwich, A. L. & Brueckner, M. Duplication/deficiency mapping of situs inversus viscerum (iv), a gene that determines left–right asymmetry in the mouse. Genomics 14, 643– 648 (1992).

    Article  CAS  Google Scholar 

  16. Asai, D. J. et al. The dynein genes of Paramecium tetraurelia: sequencies adjacent to the catalytic P-loop identify cytoplasmic and axonemal heavy chain isoforms. J. Cell Sci. 107, 839– 847 (1994).

    CAS  PubMed  Google Scholar 

  17. Brueckner, M., D'Eustachio, P. & Horwich, A. L. Linkage mapping of a mouse gene, iv, that controls left–right asymmetry of the heart and viscera. Proc. Natl Acad. Sci. USA 86, 5035– 5038 (1989).

    Article  ADS  CAS  Google Scholar 

  18. Bellomo, D., Lander, A., Harragan, I. & Brown, N. A. Cell proliferation in mammalian gastrulation: the ventral node and notochord are relatively quiescent. Dev. Dyn. 205, 471–485 (1996).

    Article  CAS  Google Scholar 

  19. Vaisberg, E. A., Grissom, P. M. & McIntosh, J. R. Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles. J. Cell Biol. 133, 831–841 (1996).

    Article  CAS  Google Scholar 

  20. Theurkauf, W. E. Microtubules and cytoplasm organization during Drosophila oogenesis. Dev. Biol. 165, 352–360 (1994).

    Article  CAS  Google Scholar 

  21. Jesuthasan, S. & Strahle, U. Dynamic microtubules and specification of the zebrafish embryonic axis. Curr. Biol. 7, 31–42 (1996 ).

    Article  Google Scholar 

  22. Danos, M. C. & Yost, H. J. Linkage of cardiac left-right asymmetry and dorsal–anterior development in Xenopus. Development 121, 1467–1474 ( 1995).

    CAS  PubMed  Google Scholar 

  23. Hyatt, B. A., Lohr, J. L. & Yost, H. J. Initiation of vertebrate left–right axis formation by maternal Vg1. Nature 384, 62– 65 (1996).

    Article  ADS  CAS  Google Scholar 

  24. Elisha, Z., Havin, L., Ringel, I. & Yisraeli, J. K. Vg1 RNA binding protein mediates the association of Vg1 RNA with microtubules in Xenopus oocytes. EMBO J. 14, 5109–5114 (1995).

    Article  CAS  Google Scholar 

  25. Brown, N. A., McCarthy, A. & Wolpert, L. Development of handed body asymmetry in mammals. Ciba Found. Symp. 162, 182–201 (1991).

    CAS  PubMed  Google Scholar 

  26. Supp, D. M., Witte, D. P., Branford, W. W., Smith, E. P. & Potter, S. S. Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility. Dev. Biol. 176, 284–299 (1996).

    Article  CAS  Google Scholar 

  27. Segre, J. A., Nemhauser, J. L., Taylor, B. A., Nadeau, J. H. & Lander, E. S. Positional cloning of the nude locus: genetic, physical, and transcription maps of the region and mutations in the mouse and rat. Genomics 28, 549–559 (1995).

    Article  CAS  Google Scholar 

  28. Kern, M. J., Witte, D. P., Valerius, M. T., Aronow, B. J. & Potter, S. S. Anovel murine homeobox gene isolated by a tissue specific PCR cloning strategy. Nucleic Acids Res. 20, 5189–5195 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. B. Vallee, M. A. Ghee and K. T. Vaughn for their comments and for providing a mouse cytoplasmic dynein cDNA probe; J. McGrath for assistance in embryo isolation; M. Lee for help with chromosome mapping; J. M. Corrales for help with cDNA cloning; K. Saalfeld, P. Groen and L. Artmeyer for in situ hybridization; A. Emley for photographic assistance; S. Bell for help with the expression studies; A. Horwich for comments and discussion; and the staff at the Keck Biotechnology Center at Yale University and at the University of Cincinnati DNA Core Facility for DNA sequencing. This work was supported by grants from the NIH (S.S.P. and D.M.S.), the American Heart Association, Ohio Division (D.P.W.), and The March of Dimes (M.B.)

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Authors and Affiliations

  1. Divisions of Development Biology, The Children's Hospital Research Foundation, Cincinnati, 45229 , Ohio, USA

    Dorothy M. Supp & S. Steven Potter

  2. Divisions of Pathology, The Children's Hospital Research Foundation, Cincinnati, 45229 , Ohio, USA

    David P. Witte

  3. Department of Pediatrics/Cardiology Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Martina Brueckner

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  1. Dorothy M. Supp
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Correspondence to Martina Brueckner.

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Supp, D., Witte, D., Potter, S. et al. Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum mice. Nature 389, 963–966 (1997). https://doi.org/10.1038/40140

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