Toyofuku Toshihiko, Zhang Hong, Kumanogoh Atsushi, Takegahara Noriko, Yabuki Masanori, Harada Koichiro, Hori Masatsugu, Kikutani Hitoshi
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nat Cell Biol. 2004 Dec;6(12):1204-11. doi: 10.1038/ncb1193. Epub 2004 Nov 14.
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.
心脏腔室的形成涉及心肌组织的动态变化，包括小梁形成和致密层的扩张。然而，调节心肌模式的位置线索仍不清楚。通过结扎丛蛋白A1受体，跨膜型信号素Sema6D调节心内膜细胞迁移。在这里，我们证明，敲低Sema6D或丛蛋白A1会导致生成小而薄的心室致密层，并导致小梁形成缺陷。在心脏中，单独的丛蛋白A1细胞外结构域的表达可以挽救由丛蛋白A1抑制诱导的小梁形成缺陷，但不能挽救由Sema6D表达缺陷导致的小梁形成缺陷。这表明Sema6D的反向信号在心肌内发生。以配体依赖的方式，Abl激酶被招募到Sema6D的细胞质尾部并被激活，导致Enabled磷酸化并从Sema6D解离。Sema6D信号的组成性激活增强了心肌细胞向小梁的迁移，而抑制则使细胞停滞在致密层内。因此，Sema6D协调致密层扩张和小梁形成，既是丛蛋白A1的配体又是受体。
