Diverse cell types of the blood are generated from the hematopoietic stem cell. The molecular mechanism by which a stem cell is permitted to differentiate towards one cell type versus another is undefined. This lineage commitment process involves a precise control of gene expression such that two daughter cells generated from a common precursor exhibit distinct global gene expression pattern from each other as well as from the parent. A breakdown in the gene expression network results in cell death or abnormal cell growth and cancer. Hence, identification and characterization of regulators of cell fate are essential for elucidating the origin of tumors and development of highly specific and novel drugs against cancer. This project is aimed at understanding the molecular mechanism of T cell lineage commitment. During T cell development two distinct classes of T cells, gamma-delta and alpha-beta T cells, are generated from a common precursor. We have identified a panel of gamma-delta or alpha-beta lineage-specific genes by global gene expression profiling of developing T cell subsets. One gamma-delta lineage specific gene called Sox13 has been found to differentially influence the development of alpha-beta and gamma-delta cells. In mice, Sox13 misexpression in alpha-beta cells can partly convert these cells to adopt a gamma-delta-lineage specific molecular program. Sox13 is the first lineage specific gene identified that modulates T cell lineage development. One of its functions during T cell development appears to be to inhibit cell proliferation. We will further define Sox13 function by purifying Sox13 expressing and non-expressing T precursor cells, and comparing how these subpopulations differentiate in vivo. This experiment will constitute the first direct examination of the existence of gamma-delta or alpha-beta lineage committed precursor subset. The mechanism of Sox13 function will be determined by testing Sox13's ability to inhibit critical biochemical pathways controlling alpha-beta lineage proliferation and by analyzing T cell developmental defects in Sox13-deficient mice that are currently under development. Finally, this proposal will identify cell-extrinsic signals that establish Sox 13 expression pattern as well as intracellular cofactors necessary for SOX 13 function. Collectively, the genetic program controlling T cell lineage commitment and maturation will be determined, allowing a better understanding of leukemogenesis.
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