The Homeoprotein Hex Regulates Hemangioblast Different*

描述（由申请人提供）：造血干细胞和内皮干细胞来源于称为成血管细胞的常见胚胎前体。调控成血管细胞分化为造血干细胞和内皮干细胞的遗传级联反应在很大程度上是未知的。许多胚胎发育是由转录因子的时间和空间表达协调调节的，例如同源异型盒（Hox）基因家族。我们和其他人分离出一个不同的Hox基因，称为Hex（或Prh），在成人中优先表达于所有骨髓和B细胞，但不表达于T细胞。在分化过程中下调。在胚胎发生过程中，Hex是内皮发育的早期标志物，并且对于内胚层器官发育是必需的。使用体外Hex -/-胚胎干（ES）细胞分化和嵌合小鼠，我们已经发现Hex对于成血管细胞分化为永久造血祖细胞是必需的。我们还发现，Hex在T细胞中的强制表达，在正常情况下不表达，抑制胸腺T细胞发育，并维持髓系标志物的表达。这些数据产生了该提议的潜在假设，即Hex调节成血管细胞向造血祖细胞的分化。这一假设将通过回答3个具体问题来检验：1）Hex诱导造血发育的生化机制是什么？2)Hex在造血发育所必需的转录因子和细胞因子的层次结构中处于什么位置？3)在胚胎发生过程中，Hex在成血管细胞分化中的作用在空间和时间上的位置是什么？阐明这些问题将阐明Hex调节第一个造血细胞形成的机制，并将其置于发育胚胎中的空间，时间和转录背景下。这也将为胚胎造血的分子调控提供新的见解。

DESCRIPTION (provided by applicant): Hematopoietic and endothelial stem cells are derived from a common embryonic precursor termed the hemangioblast. The genetic cascades that regulate differentiation of the hemangioblast to hematopoietic and endothelial stem cells are largely unknown. Much of embryonic development is coordinately regulated by temporal and spatial expression of transcription factors, such as the Homeobox (Hox) gene family. We and others isolated a divergent Hox gene termed Hex (or Prh) that in the adult is preferentially expressed in all myeloid and B-cells but not T-cells. It is down-regulated during differentiation. During embryogenesis, Hex is an early marker of endothelial development, and is essential for endodermal organ development. Using in vitro Hex -/- embryonic stem (ES) cell differentiation and chimeric mice, we have found that Hex is essential for differentiation of the hemangioblast to definitive hematopoietic progenitors. We also found that forced expression of Hex in T-cells, where it is not normally expressed, inhibited thymic T-cell development, and maintained expression of myeloid markers. These data generated the underlying hypothesis of this proposal, that Hex regulates the differentiation of the hemangioblast to hematopoietic progenitor cells. This hypothesis will be tested by answering 3 specific questions: 1) What is the biochemical mechanism by which Hex induces hematopoietic development? 2) Where does Hex fit in the hierarchy of transcription factors and cytokines that are essential for hematopoietic development? 3) What is the spatial and temporal location of Hex's function in the differentiation of the hemangioblast during embryogenesis? Answering these questions will elucidate the mechanism by which Hex regulates the formation of the first hematopoietic cells, and will place it in a spatial, temporal and transcriptional context within the developing embryo. It will also provide novel insight into the molecular regulation of embryonic hematopoiesis.