Letter | Published:

Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch

Nature volume 450, pages 285288 (08 November 2007) | Download Citation

Abstract

Laterality of the internal organs of vertebrates is determined by asymmetric Nodal signalling in the lateral plate mesoderm1. A deficiency of such signalling results in heterotaxia syndrome, characterized by anomalous laterality of visceral organs and complex congenital heart conditions1. Pitx2, the transcription factor induced by the Nodal signal, regulates left–right asymmetric morphogenesis1,2,3,4. The cellular and molecular bases of asymmetric morphogenesis remain largely unknown, however. Here we show that ablation of unilateral Pitx2 expression in mice impairs asymmetric remodelling of the branchial arch artery (BAA) system, resulting in randomized laterality of the aortic arch. Pitx2-positive cells were found not to contribute to asymmetrically remodelled arteries. Instead, Pitx2 functions in the secondary heart field5 and induces a dynamic morphological change in the outflow tract of the heart, which results in the provision of an asymmetric blood supply to the sixth BAA. This uneven distribution of blood flow results in differential signalling by both the platelet-derived growth factor receptor and vascular endothelial growth factor receptor 2. The consequent stabilization of the left sixth BAA and regression of its right counterpart underlie left-sided formation of the aortic arch. Our results therefore indicate that haemodynamics, generated by a Pitx2-induced morphological change in the outflow tract, is responsible for the asymmetric remodelling of the great arteries.

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Acknowledgements

We thank S. Iseki, A. McMahon and H. Sucov for Wnt1-Cre mice; the staff of MRC Technology in Edinburgh for technical assistance with OPT; K. Yamashita for transgene construction; K. Mochida, S. Ohishi and Y. Ikawa for general technical assistance; Primetech Corp. for technical assistance with Vevo770; and P. Soriano, T. Kubo, K. Ozono, T. Sano, T. Matsusita, S. Kogaki and the cardiologists in the Department of Pediatrics, Osaka University Medical School, for advice. This work was supported by grants (to H.H.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by CREST.

Author Contributions Project planning was mainly performed by K.Y.; most of the experiments were carried out by K.Y. and the remaining experiments by H.S. and H.H.; the manuscript was written by K.Y. and H.H.

Author information

Author notes

    • Kenta Yashiro

    Present address: Translational Cardiovascular Therapeutics, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Charterhouse Square, London EC1M 6BQ, UK

Affiliations

  1. Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan

    • Kenta Yashiro
    • , Hidetaka Shiratori
    •  & Hiroshi Hamada
  2. CREST, Japan Science and Technology Corporation (JST), 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan

    • Kenta Yashiro
    • , Hidetaka Shiratori
    •  & Hiroshi Hamada

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kenta Yashiro or Hiroshi Hamada.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Discussion 1-2, Supplementary Tables S1-S2, additional references, Supplementary Figures S1-S7 with Legends and Supplementary Videos 1-9 Legends

Videos

  1. 1.

    Supplementary Video 1

    The file contains Supplementary Video 1 which shows the appearance of a control (unligated) cultured embryo. This movie shows that the viability of the control embryos in the artery ligation experiment could not be affected.

  2. 2.

    Supplementary Video 2

    The file contains Supplementary Video 2 which shows the appearance of a ligated cultured embryo. This movie shows the ligation of the left branchial arch arteries could not affect the viability of the embryos.

  3. 3.

    Supplementary Video 3

    The file contains Supplementary Video 3 which shows the blood supply in the left BAAs of the control embryo shown in Supplementary Video 1. This movie shows the intact blood supply into the left side branchial arch arteries in the unligated embryos.

  4. 4.

    Supplementary Video 4

    The file contains Supplementary Video 4 which shows the loss of blood supply in the left BAAs of the ligated embryo shown in Supplementary Video 2. This movie shows the loss of blood supply into the left side branchial arch arteries in the ligated embryos.

  5. 5.

    Supplementary Video 5

    The file contains Supplementary Video 5 which shows the appearance of a control embryo cultured with vehicle (DMSO) alone. This movie shows that the culture condition without the inhibitors could not affect the viability of the embryos

  6. 6.

    Supplementary Video 6

    The file contains Supplementary Video 6 which shows the appearance of an embryo cultured with VEGFR inhibitor (2 μM) and AG1296 (50 μM). This movie shows that the culture condition with VEGFR inhibitor and AG1296 could not affect the viability, the appearance, and the major vessels of the embryos.

  7. 7.

    Supplementary Video 7

    The file contains Supplementary Video 7 which shows the appearance of an embryo cultured with AG1433 (10 μM).This movie shows that the culture condition with AG1433 could not affect the viability, the appearance, and the major vessels of the embryos.

  8. 8.

    Supplementary Video 8

    The file contains Supplementary Video 8 which shows the appearance of an embryo cultured with propranolol (10 μM).This movie shows that propranolol (10μM) could reduce the heart rate significantly.

  9. 9.

    Supplementary Video 9

    The file contains Supplementary Video 9 which shows the appearance of an embryo cultured with propranolol (25 μM). This movie shows that the bradicardia induced by propranolol (25μM) was more significant than by propranolol (10M).

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DOI

https://doi.org/10.1038/nature06254

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