(262g) Minimal Models of Extrinsic Regulation in Cell-Fate Decisions

In response to extracellular cues, concentrations of which can be incrementally tuned, a multipotent stem cell can make a discrete, all-or-none fate decision. Although many of the individual biochemical reactions that are critical to such cell-fate decisions are beginning to be elucidated, the network topologies that can convert these 'analog' cues into 'digital' cellular responses remain poorly understood. Here, we examine the role of positive receptor feedback in lineage specification of hematopoietic progenitors and present both deterministic and stochastic computational frameworks that link this receptor-mediated regulation with classical transcriptional regulation. Analyses of the corresponding network models elucidate novel mechanisms by which positive receptor feedback can generate discrete and stable cell fates in response to cognate extracellular ligands. Our model simulations are in good agreement with experimental findings and may provide new insights into extrinsic regulation during lineage commitment.