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共同胚胎前体。调控成血管细胞向造血干细胞和内皮干细胞分化的遗传级联在很大程度上是未知的。许多胚胎发育是由转录因子的时空表达协调调节的，如同源盒（Hox）基因家族。我们和其他人分离出一种称为Hex（或Prh）的分化Hox基因，该基因在成人中优先表达于所有髓细胞和b细胞，但不表达于t细胞。它在分化过程中被下调。在胚胎发生过程中，海克斯是内皮细胞发育的早期标志，对内胚层器官的发育至关重要。通过体外Hex -/-胚胎干（ES）细胞分化和嵌合小鼠，我们发现Hex对于成血管细胞分化为最终的造血祖细胞至关重要。我们还发现，在正常情况下不表达Hex的t细胞中，强迫表达Hex可以抑制胸腺t细胞的发育，并维持髓系标记物的表达。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个具体问题来验证：1)Hex诱导造血发育的生化机制是什么？2)在造血发育所必需的转录因子和细胞因子的层次结构中，Hex处于什么位置？3)胚胎发生过程中，Hex在成血管细胞分化中的作用在时空上处于什么位置？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、时间和转录背景中。它还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.