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Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling

Nature Cell Biology volume 6, pages 1204–1211 (2004)Cite this article

Abstract

Cardiac chamber formation involves dynamic changes in myocardial organization, including trabeculation and expansion of the compact layer1. The positional cues that regulate myocardial patterning, however, remain unclear. Through ligation of the Plexin-A1 receptor, the transmembrane-type semaphorin Sema6D regulates endocardial cell migration2. Here, we demonstrate that knockdown of either Sema6D or Plexin-A1 leads to the generation of a small, thin ventricular compact layer and to defective trabeculation. In the heart, expression of the Plexin-A1 extracellular domain alone can rescue the defective trabeculation induced by suppression of Plexin-A1, but not that resulting from defective Sema6D expression. This indicates that reverse signalling by Sema6D occurs within the myocardium. In a ligand-dependent manner, Abl kinase is recruited to the cytoplasmic tail of Sema6D and activated, resulting in phosphorylation of Enabled and dissociation from Sema6D. Constitutive activation of Sema6D signalling enhances the migration of myocardial cells into the trabeculae, whereas inhibition arrests cells within the compact layer. Thus, Sema6D coordinates both compact-layer expansion and trabeculation, functioning as both a ligand and a receptor for Plexin-A1.

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Figure 1: Truncated Plexin-A1 enhances trabecular layer formation in the cardiac ventricle.
Figure 2: Biochemical analysis of the binding of Sema6D to Abl kinase and Mena.
Figure 3: Activated Abl kinase regulates the association between Sema6D and Ena.
Figure 4: Cell sorting after mosaic expression of Sema6D–Plexin-A1 signalling components.
Figure 5: Model depicting roles of Sema6D and Plexin-A1 during cardiac morphogenesis.

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Acknowledgements

We thank K. Kubota, J. Yoshida and T. Sugimoto for their assistance, and Novartis Pharm Inc. for providing STI-571. This study was supported by research grants from the Ministry of Education, Science and Culture, Japan, which were granted to T.T., A.K. and H.K.

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Authors and Affiliations

  1. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Toshihiko Toyofuku, Hong Zhang, Masanori Yabuki, Koichiro Harada & Masatsugu Hori

  2. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Toshihiko Toyofuku, Hong Zhang, Atsushi Kumanogoh, Noriko Takegahara, Masanori Yabuki, Koichiro Harada & Hitoshi Kikutani

  3. CREST, Japan Science and Technology Corporation, Japan

    Toshihiko Toyofuku, Atsushi Kumanogoh & Hitoshi Kikutani

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  1. Toshihiko Toyofuku
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Correspondence to Hitoshi Kikutani.

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Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Table S1, Table S2 (PDF 1605 kb)

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Toyofuku, T., Zhang, H., Kumanogoh, A. et al. Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6, 1204–1211 (2004). https://doi.org/10.1038/ncb1193

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