Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation

Gloria Lee; Annie Lo; Sarah A Short; Tosti J Mankelow; Frances Spring; Stephen F Parsons; Karina Yazdanbakhsh; Narla Mohandas; David J Anstee; Joel Anne Chasis

doi:10.1182/blood-2006-03-006759

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Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation

Journal article

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Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation

Gloria Lee, Annie Lo, Sarah A Short, Tosti J Mankelow, Frances Spring, Stephen F Parsons, Karina Yazdanbakhsh, Narla Mohandas, David J Anstee and Joel Anne Chasis

Blood, Vol.108(6), pp.2064-2071

09/15/2006

DOI: 10.1182/blood-2006-03-006759

PMCID: PMC1895542

PMID: 16690966

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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. Because macrophages express alpha(V), ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knock-out mice and developed quantitative, live cell techniques for harvesting intact islands and for re-forming islands in vitro. We observed a 47% decrease in islands reconstituted from ICAM-4 null marrow compared to wild-type marrow. We also found a striking decrease in islands formed in vivo in knock-out mice. Further, peptides that block ICAM-4/alpha(V) adhesion produced a 53% to 57% 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 erythroblastic 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.

Gene Targeting

Cell Adhesion Molecules - chemistry

Protein Structure, Tertiary

Cell Adhesion Molecules - genetics

Erythroid Precursor Cells - cytology

Cell Adhesion Molecules - physiology

Bone Marrow Cells - cytology

Mice, Inbred C57BL

Cell Adhesion Molecules - deficiency

Erythroblasts - metabolism

Models, Molecular

Erythropoiesis - physiology

Mice, Knockout

DNA - genetics

Animals

Base Sequence

Erythroid Precursor Cells - metabolism

Mice

Erythroblasts - cytology

Bone Marrow Cells - metabolism

Integrin alphaV - metabolism

Erythropoiesis - genetics

Details

Title: Subtitle: Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation
Creators: Gloria Lee - Life Sciences Division, University of California, Lawrence Berkeley National Laboratory, Bldg 74, 1 Cyclotron Road, Berkeley, CA 94720, USA
Annie Lo
Sarah A Short
Tosti J Mankelow
Frances Spring
Stephen F Parsons
Karina Yazdanbakhsh
Narla Mohandas
David J Anstee
Joel Anne Chasis
Resource Type: Journal article
Publication Details: Blood, Vol.108(6), pp.2064-2071
DOI: 10.1182/blood-2006-03-006759
PMID: 16690966
PMCID: PMC1895542
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: United States
Grant note: DK 32094 / NIDDK NIH HHS\nDK 56267 / NIDDK NIH HHS
Language: English
Date published: 09/15/2006
Academic Unit: Iowa Neuroscience Institute; Immunology; Internal Medicine
Record Identifier: 9984070016902771

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