Skip to main content
PMC home page
Comparative and Functional Genomics logoLink to Comparative and Functional Genomics
. 2001 Apr;2(2):60–68. doi: 10.1002/cfg.74

Genetic Steps to Organ Laterality in Zebrafish

Jau-Nian Chen 1,2, Frauke van Bebber 3, Allan M Goldstein 1,2, Fabrizio C Serluca 1,2, Donald Jackson 1,2, Sarah Childs 1,2, George Serbedzija 1,2, Kerri S Warren 1,2, John D Mably 1,2, Per Lindahl 1,2, Alan Mayer 1,2, Pascal Haffter 3, Mark C Fishman 1,2,✉
PMCID: PMC2447199  PMID: 18628903

Abstract

All internal organs are asymmetric along the left–right axis. Here we report a genetic screen to discover mutations which perturb organ laterality. Our particular focus is upon whether, and how, organs are linked to each other as they achieve their laterally asymmetric positions. We generated mutations by ENU mutagenesis and examined F3 progeny using a cocktail of probes that reveal early primordia of heart, gut, liver and pancreas. From the 750 genomes examined, we isolated seven recessive mutations which affect the earliest left–right positioning of one or all of the organs. None of these mutations caused discernable defects elsewhere in the embryo at the stages examined. This is in contrast to those mutations we reported previously (Chen et al., 1997) which, along with left–right abnormalities, cause marked perturbation in gastrulation, body form or midline structures. We find that the mutations can be classified on the basis of whether they perturb relationships among organ laterality. In Class 1 mutations, none of the organs manifest any left–right asymmetry. The heart does not jog to the left and normally leftpredominant BMP4 in the early heart tube remains symmetric. The gut tends to remain midline. There frequently is a remarkable bilateral duplication of liver and pancreas. Embryos with Class 2 mutations have organotypic asymmetry but, in any given embryo, organ positions can be normal, reversed or randomized. Class 3 reveals a hitherto unsuspected gene that selectively affects laterality of heart. We find that visceral organ positions are predicted by the direction of the preceding cardiac jog. We interpret this as suggesting that normally there is linkage between cardiac and visceral organ laterality. Class 1 mutations, we suggest, effectively remove the global laterality signals, with the consequence that organ positions are effectively symmetrical. Embryos with Class 2 mutations do manifest linkage among organs, but it may be reversed, suggesting that the global signals may be present but incorrectly orientated in some of the embryos. That laterality decisions of organs may be independently perturbed, as in the Class 3 mutation, indicates that there are distinctive pathways for reception and organotypic interpretation of the global signals.

Full Text

The Full Text of this article is available as a PDF (185.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bisgrove B. W., Essner J. J., Yost H. J. Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development. 2000 Aug;127(16):3567–3579. doi: 10.1242/dev.127.16.3567. [DOI] [PubMed] [Google Scholar]
  2. Brown N. A., Wolpert L. The development of handedness in left/right asymmetry. Development. 1990 May;109(1):1–9. doi: 10.1242/dev.109.1.1. [DOI] [PubMed] [Google Scholar]
  3. Chen J. N., Fishman M. C. Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation. Development. 1996 Dec;122(12):3809–3816. doi: 10.1242/dev.122.12.3809. [DOI] [PubMed] [Google Scholar]
  4. Chen J. N., van Eeden F. J., Warren K. S., Chin A., Nüsslein-Volhard C., Haffter P., Fishman M. C. Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development. 1997 Nov;124(21):4373–4382. doi: 10.1242/dev.124.21.4373. [DOI] [PubMed] [Google Scholar]
  5. Chin A. J., Tsang M., Weinberg E. S. Heart and gut chiralities are controlled independently from initial heart position in the developing zebrafish. Dev Biol. 2000 Nov 15;227(2):403–421. doi: 10.1006/dbio.2000.9924. [DOI] [PubMed] [Google Scholar]
  6. Danos M. C., Yost H. J. Linkage of cardiac left-right asymmetry and dorsal-anterior development in Xenopus. Development. 1995 May;121(5):1467–1474. doi: 10.1242/dev.121.5.1467. [DOI] [PubMed] [Google Scholar]
  7. Danos M. C., Yost H. J. Role of notochord in specification of cardiac left-right orientation in zebrafish and Xenopus. Dev Biol. 1996 Jul 10;177(1):96–103. doi: 10.1006/dbio.1996.0148. [DOI] [PubMed] [Google Scholar]
  8. Kaufmann E., Knöchel W. Five years on the wings of fork head. Mech Dev. 1996 Jun;57(1):3–20. doi: 10.1016/0925-4773(96)00539-4. [DOI] [PubMed] [Google Scholar]
  9. Kosaki K., Casey B. Genetics of human left-right axis malformations. Semin Cell Dev Biol. 1998 Feb;9(1):89–99. doi: 10.1006/scdb.1997.0187. [DOI] [PubMed] [Google Scholar]
  10. Levin M., Johnson R. L., Stern C. D., Kuehn M., Tabin C. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell. 1995 Sep 8;82(5):803–814. doi: 10.1016/0092-8674(95)90477-8. [DOI] [PubMed] [Google Scholar]
  11. Levin M., Mercola M. Gap junctions are involved in the early generation of left-right asymmetry. Dev Biol. 1998 Nov 1;203(1):90–105. doi: 10.1006/dbio.1998.9024. [DOI] [PubMed] [Google Scholar]
  12. Lowe L. A., Supp D. M., Sampath K., Yokoyama T., Wright C. V., Potter S. S., Overbeek P., Kuehn M. R. Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature. 1996 May 9;381(6578):158–161. doi: 10.1038/381158a0. [DOI] [PubMed] [Google Scholar]
  13. Meno C., Shimono A., Saijoh Y., Yashiro K., Mochida K., Ohishi S., Noji S., Kondoh H., Hamada H. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell. 1998 Aug 7;94(3):287–297. doi: 10.1016/s0092-8674(00)81472-5. [DOI] [PubMed] [Google Scholar]
  14. Milewski W. M., Duguay S. J., Chan S. J., Steiner D. F. Conservation of PDX-1 structure, function, and expression in zebrafish. Endocrinology. 1998 Mar;139(3):1440–1449. doi: 10.1210/endo.139.3.5768. [DOI] [PubMed] [Google Scholar]
  15. Mullins M. C., Hammerschmidt M., Haffter P., Nüsslein-Volhard C. Large-scale mutagenesis in the zebrafish: in search of genes controlling development in a vertebrate. Curr Biol. 1994 Mar 1;4(3):189–202. doi: 10.1016/s0960-9822(00)00048-8. [DOI] [PubMed] [Google Scholar]
  16. Mullins M. C., Hammerschmidt M., Kane D. A., Odenthal J., Brand M., van Eeden F. J., Furutani-Seiki M., Granato M., Haffter P., Heisenberg C. P. Genes establishing dorsoventral pattern formation in the zebrafish embryo: the ventral specifying genes. Development. 1996 Dec;123:81–93. doi: 10.1242/dev.123.1.81. [DOI] [PubMed] [Google Scholar]
  17. Odenthal J., Nüsslein-Volhard C. fork head domain genes in zebrafish. Dev Genes Evol. 1998 Jul;208(5):245–258. doi: 10.1007/s004270050179. [DOI] [PubMed] [Google Scholar]
  18. Oh S. P., Li E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 1997 Jul 15;11(14):1812–1826. doi: 10.1101/gad.11.14.1812. [DOI] [PubMed] [Google Scholar]
  19. Ramsdell A. F., Yost H. J. Molecular mechanisms of vertebrate left-right development. Trends Genet. 1998 Nov;14(11):459–465. doi: 10.1016/s0168-9525(98)01599-6. [DOI] [PubMed] [Google Scholar]
  20. Rodríguez Esteban C., Capdevila J., Economides A. N., Pascual J., Ortiz A., Izpisúa Belmonte J. C. The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature. 1999 Sep 16;401(6750):243–251. doi: 10.1038/45738. [DOI] [PubMed] [Google Scholar]
  21. Schilling T. F., Concordet J. P., Ingham P. W. Regulation of left-right asymmetries in the zebrafish by Shh and BMP4. Dev Biol. 1999 Jun 15;210(2):277–287. doi: 10.1006/dbio.1999.9214. [DOI] [PubMed] [Google Scholar]
  22. Supp D. M., Witte D. P., Potter S. S., Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature. 1997 Oct 30;389(6654):963–966. doi: 10.1038/40140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tsukui T., Capdevila J., Tamura K., Ruiz-Lozano P., Rodriguez-Esteban C., Yonei-Tamura S., Magallón J., Chandraratna R. A., Chien K., Blumberg B. Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11376–11381. doi: 10.1073/pnas.96.20.11376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yokouchi Y., Vogan K. J., Pearse R. V., 2nd, Tabin C. J. Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell. 1999 Sep 3;98(5):573–583. doi: 10.1016/s0092-8674(00)80045-8. [DOI] [PubMed] [Google Scholar]
  25. Yokoyama T., Copeland N. G., Jenkins N. A., Montgomery C. A., Elder F. F., Overbeek P. A. Reversal of left-right asymmetry: a situs inversus mutation. Science. 1993 Apr 30;260(5108):679–682. doi: 10.1126/science.8480178. [DOI] [PubMed] [Google Scholar]

Articles from Comparative and Functional Genomics are provided here courtesy of Wiley

RESOURCES