Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2

  1. Toshihiko Toyofuku1,2,3,5,
  2. Hong Zhang1,2,5,
  3. Atsushi Kumanogoh2,3,
  4. Noriko Takegahara2,
  5. Fumikazu Suto4,
  6. Junko Kamei1,2,
  7. Kazuhiro Aoki1,
  8. Masanori Yabuki1,2,
  9. Masatsugu Hori1,
  10. Hajime Fujisawa4, and
  11. Hitoshi Kikutani2,3,6
  1. 1Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; 2Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; 3Core Research For Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan; 4Division of Biological Science, Nagoya University Graduate School of Science, Chikusa-ku, Nagoya 464-8602, Japan

Abstract

Semaphorins, originally identified as axon guidance factors in the nervous system, play integral roles in organogenesis. Here, we demonstrate a critical involvement of Sema6D in cardiac morphogenesis. Ectopic expression of Sema6D or RNA interference against Sema6D induces expansion or narrowing of the ventricular chamber, respectively, during chick embryonic development. Sema6D also exerts region-specific activities on cardiac explants, a migration-promoting activity on outgrowing cells from the conotruncal segment, and a migration-inhibitory activity on those from the ventricle. Plexin-A1 mediates these activities as the major Sema6D-binding receptor. Plexin-A1 forms a receptor complex with vascular endothelial growth factor receptor type 2 in the conotruncal segment or with Off-track in the ventricle segment; these complexes are responsible for the effects of Sema6D on the respective regions. Thus, the differential association of Plexin-A1 with additional receptor components entitles Sema6D to exert distinct biological activities at adjacent regions. This is crucial for complex cardiac morphogenesis.

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Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1167304.

  • 5 These authors contributed equally to this work.

  • 6 Corresponding author.

    6 E-MAIL kikutani{at}ragtime.biken.osaka-u.ac.jp; FAX 81-06-6875-4465.

    • Accepted January 16, 2004.
    • Received November 4, 2003.
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