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Title: Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation

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), animmunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counter receptors. 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 produced 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 erythroblasticmore » island formation and their functional role in regulating erythropoiesis.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director. Office of Science. Office of Biological andEnvironmental Research. Life Sciences Division; National Institutes ofHealth Grants DK56267 and DK32094; National Health Service Research andDevelopment Directorate/UK
OSTI Identifier:
891632
Report Number(s):
LBNL-59807
Journal ID: ISSN 0006-4971; BLOOAW; R&D Project: L0145; BnR: 400412000; TRN: US200622%%274
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Blood; Journal Volume: 108; Journal Issue: 6; Related Information: Journal Publication Date: 09/15/2006
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ADHESION; ADHESIVES; APOPTOSIS; BONE MARROW; BONE MARROW CELLS; ERYTHROPOIESIS; FUNCTIONALS; GENES; HARVESTING; IN VITRO; IN VIVO; MACROPHAGES; MICE; PEPTIDES

Citation Formats

Lee, Gloria, Lo, Annie, Short, Sarah A., Mankelow, Tosti J., Spring, Frances, Parsons, Stephen F., Mohandas, Narla, Anstee, David J., and Chasis, Joel Anne. Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation. United States: N. p., 2006. Web. doi:10.1182/blood-2006-03-006759.
Lee, Gloria, Lo, Annie, Short, Sarah A., Mankelow, Tosti J., Spring, Frances, Parsons, Stephen F., Mohandas, Narla, Anstee, David J., & Chasis, Joel Anne. Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation. United States. doi:10.1182/blood-2006-03-006759.
Lee, Gloria, Lo, Annie, Short, Sarah A., Mankelow, Tosti J., Spring, Frances, Parsons, Stephen F., Mohandas, Narla, Anstee, David J., and Chasis, Joel Anne. Wed . "Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation". United States. doi:10.1182/blood-2006-03-006759. https://www.osti.gov/servlets/purl/891632.
@article{osti_891632,
title = {Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation},
author = {Lee, Gloria and Lo, Annie and Short, Sarah A. and Mankelow, Tosti J. and Spring, Frances and Parsons, Stephen F. and Mohandas, Narla and Anstee, David J. and Chasis, Joel Anne},
abstractNote = {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), animmunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counter receptors. 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 produced 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.},
doi = {10.1182/blood-2006-03-006759},
journal = {Blood},
number = 6,
volume = 108,
place = {United States},
year = {Wed Feb 15 00:00:00 EST 2006},
month = {Wed Feb 15 00:00:00 EST 2006}
}