Letter | Published:

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

Nature volume 389, pages 963966 (30 October 1997) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Visceral inversion and associated anomalies in the mouse. J. Hered. 50, 9– 13 (1959).

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    , & Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124, 1465– 1472 (1997).

  8. 8.

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

  9. 9.

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

  10. 10.

    & Dyneins: molecular structure and cellular function. Annu. Rev. Cell Biol. 10, 339–372 (1994).

  11. 11.

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

  12. 12.

    , & Identification and molecular evolution of new dynein-like protein sequences in rat brain. J. Cell Sci. 108, 1883–1893 (1995).

  13. 13.

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

  14. 14.

    , , & Identification of seven rat axonemal dynein heavy chain genes: expression during ciliated cell differentiation. Mol. Biol. Cell 7, 71–79 (1996).

  15. 15.

    , & Duplication/deficiency mapping of situs inversus viscerum (iv), a gene that determines left–right asymmetry in the mouse. Genomics 14, 643– 648 (1992).

  16. 16.

    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).

  17. 17.

    , & 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).

  18. 18.

    , , & Cell proliferation in mammalian gastrulation: the ventral node and notochord are relatively quiescent. Dev. Dyn. 205, 471–485 (1996).

  19. 19.

    , & Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles. J. Cell Biol. 133, 831–841 (1996).

  20. 20.

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

  21. 21.

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

  22. 22.

    & Linkage of cardiac left-right asymmetry and dorsal–anterior development in Xenopus. Development 121, 1467–1474 ( 1995).

  23. 23.

    , & Initiation of vertebrate left–right axis formation by maternal Vg1. Nature 384, 62– 65 (1996).

  24. 24.

    , , & Vg1 RNA binding protein mediates the association of Vg1 RNA with microtubules in Xenopus oocytes. EMBO J. 14, 5109–5114 (1995).

  25. 25.

    , & Development of handed body asymmetry in mammals. Ciba Found. Symp. 162, 182–201 (1991).

  26. 26.

    , , , & 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).

  27. 27.

    , , , & 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).

  28. 28.

    , , , & Anovel murine homeobox gene isolated by a tissue specific PCR cloning strategy. Nucleic Acids Res. 20, 5189–5195 (1992).

Download references

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.)

Author information

Affiliations

  1. *Divisions of Development Biology and

    • Dorothy M. Supp
    •  & S. Steven Potter
  2. †Pathology, The Children's Hospital Research Foundation, Cincinnati, Ohio 45229 , USA

    • David P. Witte
  3. ‡Department of Pediatrics/Cardiology, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Martina Brueckner

Authors

  1. Search for Dorothy M. Supp in:

  2. Search for David P. Witte in:

  3. Search for S. Steven Potter in:

  4. Search for Martina Brueckner in:

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/40140

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.