Negative autoregulation by FAS mediates robust fetal erythropoiesis

• Published in: PLoS biology Vol. 5; no. 10; p. e252
• Main Authors: Socolovsky, Merav, Murrell, Michael, Liu, Ying, Pop, Ramona, Porpiglia, Ermelinda, Levchenko, Andre
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2007; Public Library of Science (PLoS)
• Subjects: Algorithms; Animals; Apoptosis; Apoptosis - physiology; Cell Differentiation; Cell Separation; Cloning; Computational Biology; Developmental Biology; Effect of alcohol on; Embryos; Erythrocytes - cytology; Erythrocytes - metabolism; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - metabolism; Erythropoiesis - physiology; Fas Ligand Protein - metabolism; fas Receptor - metabolism; Feedback, Physiological; Fetal alcohol syndrome; Fetus; Fetus - embryology; Fetus - metabolism; Flow Cytometry; Gene expression; Hematology; Homeostasis - physiology; Ligands; Liver; Liver - embryology; Liver - metabolism; Mathematics; Mice; Mice, Inbred C57BL; None; Ordinary differential equations; Signal Transduction; United States; Erythropoiesis; Signal Transduction; Cell Separation; Liver; Mice, Inbred C57BL; Erythrocytes; Homeostasis; Antigens, CD95; Fas Ligand Protein; Feedback, Physiological; Algorithms; Animals; Flow Cytometry; Erythroid Precursor Cells; Fetus; Cell Differentiation; Mice; Apoptosis
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0050252

Tissue development is regulated by signaling networks that control developmental rate and determine ultimate tissue mass. Here we present a novel computational algorithm used to identify regulatory feedback and feedforward interactions between progenitors in developing erythroid tissue. The algorithm makes use of dynamic measurements of red cell progenitors between embryonic days 12 and 15 in the mouse. It selects for intercellular interactions that reproduce the erythroid developmental process and endow it with robustness to external perturbations. This analysis predicts that negative autoregulatory interactions arise between early erythroblasts of similar maturation stage. By studying embryos mutant for the death receptor FAS, or for its ligand, FASL, and by measuring the rate of FAS-mediated apoptosis in vivo, we show that FAS and FASL are pivotal negative regulators of fetal erythropoiesis, in the manner predicted by the computational model. We suggest that apoptosis in erythroid development mediates robust homeostasis regulating the number of red blood cells reaching maturity.