(175ah) Modeling of Notch and PU.1 Regulation in T-Cell Vs Myeloid Differentiation

Development of T-cell lineage depends on the temporal and quantitative coordination of numerous regulatory molecules needed to promote T-cell development as well as exclude alternative developmental pathways. The final excluded alternative pathway is myeloid differentiation, which is decisively eliminated only when the thymic precursor transits from the DN2a to DN2b stage of full T-cell commitment. Herein, we have generated ordinary differential equations based on Notch and PU.1 regulation for T-cell vs Myeloid differentiation.

The T-cell vs myeloid differentiation can be viewed largely as a competition between the T-cell-promoting effects of Notch signaling, and the pro-myeloid effects of PU.1 target gene activation. For example, downregulation of PU.1 and high Notch exposure ensure progression along the T-cell pathway; high PU.1 expression in the absence of Notch ligand favors myeloid development. We have modeled Notch-PU.1 dynamics as a competition between two species. We show that presence of Notch or PU.1 produces the bi-stability in the system, forcing the system to progress to one or the other alternative steady state (T-cell or myeloid). Our model is able to qualitatively reproduce the experimental results observed exploring both absolute and temporally-graded levels of regulation by Notch and PU.1.