Socolovsky Merav, Murrell Michael, Liu Ying, Pop Ramona, Porpiglia Ermelinda, Levchenko Andre
Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Biol. 2007 Oct;5(10):e252. 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.
组织发育受信号网络调控，该网络控制发育速率并决定最终的组织质量。在此，我们展示了一种新颖的计算算法，用于识别发育中的红细胞组织中祖细胞之间的调控反馈和前馈相互作用。该算法利用了小鼠胚胎第12天至15天期间红细胞祖细胞的动态测量数据。它选择能够重现红细胞发育过程并使其对外部扰动具有稳健性的细胞间相互作用。该分析预测，相似成熟阶段的早期成红细胞之间会出现负向自调节相互作用。通过研究死亡受体FAS或其配体FASL基因敲除的胚胎，并测量体内FAS介导的凋亡速率，我们发现FAS和FASL是以计算模型预测的方式成为胎儿红细胞生成的关键负调节因子。我们认为，红细胞发育中的凋亡介导了强大的稳态，调节着成熟红细胞的数量。
