Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche

Establishment of cell-cell adhesion is crucial in embryonic development as well as within the stem cell niches of an adult. Adhesion between macrophages and erythroblasts is required for the formation of erythroblastic islands, specialized niches where erythroblasts proliferate and differentiate to...

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Bibliographic Details
Published in:Cell death and differentiation 2016-08, Vol.23 (8), p.1322-1330
Main Authors: Anselmo, A, Lauranzano, E, Soldani, C, Ploia, C, Angioni, R, D'amico, G, Sarukhan, A, Mazzon, C, Viola, A
Format: Article
Language:English
Subjects:
Adults
Agrin - deficiency
Agrin - genetics
Agrin - metabolism
Animals
Blood
Bone marrow
Cell adhesion & migration
Cell Adhesion - physiology
Cell death
Cell Survival
Erythrocytes - cytology
Erythrocytes - metabolism
Extracellular matrix
Heparan sulfate
Hyaluronan Receptors - metabolism
Integrin alpha5beta1 - metabolism
Kinases
Ligands
Megakaryocyte Progenitor Cells - cytology
Megakaryocyte Progenitor Cells - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Fluorescence
Morphology
Original Paper
Phosphorylation
Receptor, EphB1 - metabolism
Receptors, LDL - metabolism
Signal Transduction - physiology
Spleen
Spleen - pathology
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Summary:Establishment of cell-cell adhesion is crucial in embryonic development as well as within the stem cell niches of an adult. Adhesion between macrophages and erythroblasts is required for the formation of erythroblastic islands, specialized niches where erythroblasts proliferate and differentiate to produce red blood cells throughout life. The Eph family is the largest known family of receptor tyrosine kinases (RTKs) and controls cell adhesion, migration, invasion and morphology by modulating integrin and adhesion molecule activity and by modifying the actin cytoskeleton. Here, we identify the proteoglycan agrin as a novel regulator of Eph receptor signaling and characterize a novel mechanism controlling cell-cell adhesion and red cell development within the erythroid niche. We demonstrate that agrin induces clustering and activation of EphB1 receptors on developing erythroblasts, leading to the activation of α5β1 integrins. In agreement, agrin knockout mice display severe anemia owing to defective adhesion to macrophages and impaired maturation of erythroid cells. These results position agrin-EphB1 as a novel key signaling couple regulating cell adhesion and erythropoiesis.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2016.10