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ASCB 2007 American Society for Cell Biology
Poster: Sunday, December 2, 2007, program 547, board B484
Presented 1:30p-3:00p by Tim Otter.
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STAT5 and Notch-mediated Lineage Commitment in
Virtual Lymphocyte Models

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Abstract
We have designed and built in silico models suitable for analyzing mechanisms of lineage commitment in early lymphocyte progenitor (ELP) cells. Virtual molecules, genes, gene regulatory networks, and pathways are represented in a cell-based computational architecture that grows and differentiates a population of lineage-committed B cells and T cells according to the local abundance of signaling ligands. To establish the lineage commitment potential of virtual ELPs, we exposed 10x10 fixed grids of ELP cells to orthogonal gradients of Notch and IL7 ligands. Cells near the Notch source became T cells and cells near the IL7 source became B cells, but when the concentrations of both signaling molecules were low, ELPs remained uncommitted. Uncommitted cells pushed toward the Notch source or toward the IL7 source committed appropriately, and any commitment was irreversible: T cells displaced toward higher IL7 concentrations or B cells exposed to higher Notch levels retained their original commitment decision. In separate experiments, we studied the molecular contents of transgenic virtual ELP progeny to ascertain early patterns of gene expression and gene product abundance that determine whether a particular cell commits to T cell or B cell lineage. By simultaneously monitoring the intracellular concentrations of phosphorylated STAT5 (STAT5P), Notch, and two lineage specific markers in 188 ELP progeny exposed to a heterogeneous landscape of Notch ligand, we have inferred that initial intensity of Notch- versus STAT5- dependent signals control lineage commitment. Higher Notch and lower STAT5P produce T cells. Finally, varying the strength of promotion of transgenic constitutive STAT5P expression in silico predicts that stronger promotion favors production of B cells. We are verifying these results in vivo using transgenic mice which express different levels of a constitutively active STAT5 transgene.


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