title: Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche.
abstract: 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.
authors.affiliation: Humanitas Clinical and Research Centre, Rozzano (Milan), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Humanitas Clinical and Research Centre, Rozzano (Milan), Italy.|Biomedical Sciences Department, University of Padua, Padua, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Lauranzano
authors.affiliation: Humanitas Clinical and Research Centre, Rozzano (Milan), Italy.
authors.forename: C
authors.initials: C
authors.lastname: Soldani
authors.affiliation: Humanitas Clinical and Research Centre, Rozzano (Milan), Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ploia
authors.affiliation: Biomedical Sciences Department, University of Padua, Padua, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Angioni
authors.affiliation: Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM/San Gerardo Hospital, Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: D'amico
authors.affiliation: INSERM, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Sarukhan
authors.affiliation: Humanitas Clinical and Research Centre, Rozzano (Milan), Italy.|Biomedical Sciences Department, University of Padua, Padua, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mazzon
authors.affiliation: Biomedical Sciences Department, University of Padua, Padua, Italy.|Venetian Institute of Molecular Medicine, Padova (VIMM), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Viola
mesh_terms: D018171:Agrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002470:Cell Survival; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D026502:LDL-Receptor Related Proteins; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D036225:Receptor, EphB1 / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000473:pathology
chemical_list: D018171:Agrin; D018960:Hyaluronan Receptors; D039081:Integrin alpha5beta1; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D011973:Receptors, LDL; D036225:Receptor, EphB1