Regulation of T cell development by SOX13

描述（申请人提供）：造血干细胞产生多种血液细胞类型。允许干细胞向一种细胞类型分化而不是向另一种细胞类型分化的分子机制尚未确定。该谱系定型过程涉及基因表达的精确控制，使得由共同前体产生的两个子细胞表现出彼此以及与亲本不同的全局基因表达模式。基因表达网络的崩溃导致细胞死亡或异常细胞生长和癌症。因此，鉴定和表征细胞命运的调节剂对于阐明肿瘤的起源和开发高度特异性和新颖的抗癌药物至关重要。该项目旨在了解T细胞谱系定型的分子机制。在T细胞发育过程中，两种不同类型的T细胞，γ-δ和α-β T细胞，由共同的前体产生。我们已经通过发育中T细胞亚群的全局基因表达谱鉴定了一组γ-δ或α-β谱系特异性基因。一种称为Sox 13的γ-δ谱系特异性基因被发现对α-β和γ-δ细胞的发育有不同的影响。在小鼠中，α-β细胞中Sox 13的错误表达可以部分转化这些细胞，使其采用γ-δ谱系特异性分子程序。Sox 13是第一个被鉴定的调节T细胞谱系发育的谱系特异性基因。它在T细胞发育过程中的功能之一似乎是抑制细胞增殖。我们将通过纯化表达和不表达Sox 13的T前体细胞，并比较这些亚群如何在体内分化，进一步定义Sox 13的功能。该实验将构成对γ-δ或α-β谱系定向前体亚群存在的第一次直接检查。Sox 13功能的机制将通过测试Sox 13抑制控制α-β谱系增殖的关键生化途径的能力以及通过分析目前正在开发的Sox 13缺陷小鼠中的T细胞发育缺陷来确定。最后，该建议将确定建立Sox 13表达模式的细胞外信号以及Sox 13功能所需的细胞内辅因子。总的来说，控制T细胞谱系定型和成熟的遗传程序将被确定，从而更好地理解白血病发生。

DESCRIPTION (provided by applicant): 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.