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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.

Semaphorins, originally identified as axon guidance facto s in the nervous system, play integral roles in organogenesis. Here, we demonstrate a critical involvement of Sema6D in cardiac morphogenesis. Ectopic expression of Sema6D o 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.

Pubmed ID: 14977921


  • Toyofuku T
  • Zhang H
  • Kumanogoh A
  • Takegahara N
  • Suto F
  • Kamei J
  • Aoki K
  • Yabuki M
  • Hori M
  • Fujisawa H
  • Kikutani H


Genes & development

Publication Data

February 15, 2004

Associated Grants


Mesh Terms

  • Animals
  • Axons
  • Embryonic and Fetal Development
  • Gene Silencing
  • Heart
  • Heart Conduction System
  • Mice
  • Morphogenesis
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Peptide
  • Semaphorins
  • Vascular Endothelial Growth Factor Receptor-2