1. Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan
2. CREST, Japan Science and Technology Corporation (JST), 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan
3. 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

Correspondence to: Kenta Yashiro^1,2,3Hiroshi Hamada^1,2 Correspondence and requests for materials should be addressed to K.Y. (Email: k.yashiro@qmul.ac.uk) or H.H. (Email: hamada@fbs.osaka-u.ac.jp).

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 morphogenesis^{1, 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.

1. Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan
2. CREST, Japan Science and Technology Corporation (JST), 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan
3. 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

Correspondence to: Kenta Yashiro^1,2,3Hiroshi Hamada^1,2 Correspondence and requests for materials should be addressed to K.Y. (Email: k.yashiro@qmul.ac.uk) or H.H. (Email: hamada@fbs.osaka-u.ac.jp).

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