Negative autoregulation by FAS mediates robust fetal erythropoiesis.
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.
Socolovsky
Merav
M
Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. merav.socolovsky@umassmed.edu
Murrell
Michael
M
Liu
Ying
Y
Pop
Ramona
R
Porpiglia
Ermelinda
E
Levchenko
Andre
A
D000465:Algorithms; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation; D002469:Cell Separation; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D053222:Fas Ligand Protein / Q000378:metabolism*; D025461:Feedback, Physiological; D005333:Fetus / Q000196:embryology / Q000378:metabolism*; D005434:Flow Cytometry; D006706:Homeostasis / Q000502:physiology*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D019014:fas Receptor