Targeted Gene Deletion Demonstrates that Cell Adhesion Molecule ICAM-4 is Critical for Erythroblastic Island Formation
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Targeted Gene Deletion Demonstrates that Cell Adhesion Molecule ICAM-4 is Critical for Erythroblastic Island Formation

  • Author(s): Lee, Gloria
  • Lo, Annie
  • Short, Sarah A.
  • Mankelow, Tosti J.
  • Spring, Frances
  • Parsons, Stephen F.
  • Mohandas, Narla
  • Anstee, David J.
  • Chasis, Joel Anne
  • et al.
Abstract

Erythroid progenitors differentiate in erythroblastic islands, bone marrow niches composed of erythroblasts surrounding a central macrophage. Evidence suggests that within islands adhesive interactions regulate erythropoiesis and apoptosis. We are exploring whether erythroid intercellular adhesion molecule-4 (ICAM-4), an immunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counterreceptors. Since macrophages express alpha V, ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knockout mice and developed quantitative, live cell techniques for harvesting intact islands and for reforming islands in vitro. We observed a 47 percent decrease in islands reconstituted from ICAM-4 null marrow compared to wild type. We also found a striking decrease in islands formed in vivo in knockout mice. Further, peptides that block ICAM-4 alpha V adhesion pro duced a 53-57 percent decrease in reconstituted islands, strongly suggesting that ICAM-4 binding to macrophage alpha V functions in island integrity. Importantly, we documented that alpha V integrin is expressed in macrophages isolated from erythro blastic islands. Collectively, these data provide convincing evidence that ICAM-4 is critical in erythroblastic island formation via ICAM-4/alpha V adhesion and also demonstrate that the novel experimental strategies we developed will be valuable in exploring molecular mechanisms of erythroblastic island formation and their functional role in regulating erythropoiesis.

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