The Homeoprotein Hex Regulates Hemangioblast Different*

描述(申请人提供)：造血干细胞和内皮干细胞来自一种常见的胚胎前体细胞，称为血管母细胞。调节血管母细胞向造血细胞和内皮干细胞分化的基因级联机制在很大程度上是未知的。许多胚胎发育受到转录因子的时间和空间表达的协调调节，如同源盒(Homeobox，HOX)基因家族。我们和其他人分离出了一种名为Hex(或PRH)的分化HOX基因，该基因在成人中优先表达于所有髓系细胞和B细胞，但不表达于T细胞。在分化过程中，它被下调。在胚胎发育过程中，Hex是内皮发育的早期标志，对内胚层器官发育是必不可少的。利用体外六角/胚胎干细胞分化和嵌合体小鼠，我们发现六角形核对于血管母细胞向特定的造血祖细胞的分化是必不可少的。我们还发现，强制在T细胞中表达Hex，抑制了胸腺T细胞的发育，并维持了髓系标志的表达，而在T细胞中它不是正常表达的。这些数据产生了这一提议的基本假设，即Hex调节血管母细胞向造血祖细胞的分化。这一假说将通过回答三个具体问题来检验：1)Hex诱导造血发育的生化机制是什么？2)Hex在转录因子和细胞因子中的位置是什么？3)Hex在胚胎发育过程中血管母细胞分化中的作用在什么空间和时间上？回答这些问题将阐明Hex调节第一批造血细胞形成的机制，并将其置于发育中的胚胎的空间、时间和转录环境中。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.