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ZFIN ID: ZDB-PUB-090716-12
Angiomotin-Like Protein 1 Controls Endothelial Polarity and Junction Stability During Sprouting Angiogenesis
Zheng, Y., Vertuani, S., Nyström, S., Audebert, S., Meijer, I., Tegnebratt, T., Borg, J.P., Uhlén, P., Majumdar, A., and Holmgren, L.
Date: 2009
Source: Circulation research   105(3): 260-270 (Journal)
Registered Authors: Majumdar, Arindam
Keywords: AmotL1, polarity, migration, junction stability, zebrafish
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Cattle
  • Cell Adhesion/physiology
  • Cell Line
  • Cell Movement/physiology
  • Cell Polarity/physiology*
  • Endothelium, Vascular/cytology*
  • Endothelium, Vascular/metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Intercellular Junctions/metabolism*
  • Intercellular Signaling Peptides and Proteins/genetics
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice
  • Microfilament Proteins/genetics
  • Microfilament Proteins/metabolism
  • Molecular Sequence Data
  • Neovascularization, Physiologic/physiology*
  • PDZ Domains/genetics
  • Protein Isoforms/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 19590046 Full text @ Circ. Res.
Rationale: We have previously shown that angiomotin (Amot) is essential for endothelial cell migration during mouse embryogenesis. However, approximately 5% of Amot knockout mice survived without any detectable vascular defects. Amot-like 1 (AmotL1) potentially compensates for the absence of Amot as it is 62% homologous to Amot and exhibits similar expression pattern in endothelial cells. Objective: Here, we report the identification of a novel isoform of AmotL1 that controls endothelial cell polarization and directional migration. Methods and Results: Small interfering RNA-mediated silencing of AmotL1 in mouse aortic endothelial cells caused a significant reduction in migration. In confluent mouse pancreatic islet endothelial cells (MS-1), AmotL1 colocalized with Amot to tight junctions. Small interfering RNA knockdown of both Amot and AmotL1 in MS-1 cells exhibited an additive effect on increasing paracellular permeability compared to that of knocking down either Amot or AmotL1, indicating both proteins were required for proper tight junction activity. Moreover, as visualized using high-resolution 2-photon microscopy, the morpholino-mediated knockdown of amotl1 during zebrafish embryogenesis resulted in vascular migratory defect of intersegmental vessels with strikingly decreased junction stability between the stalk cells and the aorta. However, the phenotype was quite distinct from that of amot knockdown which affected polarization of the tip cells of intersegmental vessels. Double knockdown resulted in an additive phenotype of depolarized tip cells with no or decreased connection of the stalk cells to the dorsal aorta. Conclusions: These results cumulatively validate that Amot and AmotL1 have similar effects on endothelial migration and tight junction formation in vitro. However, in vivo Amot appears to control the polarity of vascular tip cells whereas AmotL1 mainly affects the stability of cell-cell junctions of the stalk cells.