Negative Autoregulation by FAS Mediates Robust Fetal Erythropoiesis

Merav Socolovsky, Michael Murrell, Ying Liu, Ramona Pop, Ermelinda Porpiglia and Andre Levchenko

PLOS Biology, 2007, vol. 5, issue 10, 1-16

Abstract: 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. : The factors that control the rate of tissue growth during development are largely unknown. During embryogenesis, the formation of anucleated red blood cells (erythropoiesis) begins in the liver, with a dramatic expansion in erythropoietic tissue mass, occurring ten times faster than overall embryonic growth. We hypothesized that a network of cell–cell interactions within the erythroid microenvironment regulates this growth burst. To identify these regulatory interactions, we made use of the empirical finding that developmental processes are relatively robust to environmental perturbations. We determined how the frequency of erythroid progenitors in each of four sequential differentiation states varies during early development in vivo. We then modeled this behavior, and computationally selected those interactions that endow the network with resistance to external perturbations. This analysis predicted that erythroblasts in “state 2” of differentiation negatively regulate each other. We found that this autoregulatory interaction is mediated by the death receptor FAS and its ligand, FASL, which are co-expressed in state 2 cells. FAS-mediated cell death occurs only when the frequency of state 2 cells is high enough to permit their sufficient proximity. In this manner, FAS-mediated apoptosis dampens the initially rapid expansion of state 2 cells, and buffers unexpected fluctuations in their number, contributing to the system's robustness. We propose that a similar approach could be used to identify intercellular interactions in other rapidly growing tissues. A novel computational algorithm is used to identify regulatory feedback and feedforward interactions between progenitors in developing erythroid tissue.

Date: 2007
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:0050252

DOI: 10.1371/journal.pbio.0050252

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