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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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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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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DOI: https://doi.org/10.1038/40140
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