title: Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling.
abstract: Cardiac chamber formation involves dynamic changes in myocardial organization, including trabeculation and expansion of the compact layer. 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 migration. 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Noriko
authors.initials: N
authors.lastname: Takegahara
authors.forename: Masanori
authors.initials: M
authors.lastname: Yabuki
authors.forename: Koichiro
authors.initials: K
authors.lastname: Harada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism; D038081:Organogenesis / Q000502:physiology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D039961:Semaphorins / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C092744:ENA-VASP proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D016374:Oncogene Proteins v-abl; C492114:Plxna1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C483479:Sema6d protein, mouse; D039961:Semaphorins