Biochemistry of Leukemia Virus Core Binding Factor

描述（由申请人提供）：Runx1-CBFbeta转录因子是所有确定的造血细胞出现所必需的。它是胚胎中造血干细胞和祖细胞产生部位的最早特异性标记物。Runx1在内皮细胞、间充质细胞、主动脉内造血集群以及所有造血祖细胞和可移植干细胞中表达。我们假设Runx1-CBFbeta是胎儿发育过程中“造血内皮细胞”和造血细胞之间过渡所必需的，至少部分是必需的。然而，如果在成年小鼠中删除Runx1，在造血建立后，长期再生的造血干细胞持续存在，承诺的红细胞、髓细胞和巨核细胞祖细胞数量增加，红细胞和终末粒细胞分化均正常。因此，Runx1-CBFbeta在胎儿中建立造血功能是绝对需要的，而不是在成人中维持造血功能的所有方面。我们的目标之一是定义发育窗口和细胞类型，其中需要Runx1-CBFbeta来指定概念中的最终造血。第二个目标是跟进最近的发现，即胎盘可能是造血干细胞的来源。我们将确定造血干细胞在胎盘中的位置，以及它们是否与尿囊或胎盘迷宫中的内皮细胞分化。最后，我们将尝试确定在受孕过程中诱导Runx1第一波表达和最终造血的信号来源。我们将专门研究Hedgehog基因（斑马鱼最终造血所需的信号级联的上游成分）是否激活Runx1表达和小鼠受孕中的最终造血。综上所述，这些目标将有助于我们理解在小鼠妊娠期建立最终造血的最早事件，并有助于指导在体外从胚胎来源产生血细胞的努力。

DESCRIPTION (provided by applicant): The Runx1-CBFbeta transcription factor is required for the emergence of all definitive hematopoietic cells. It is the earliest specific marker of sites from which hematopoietic stem and progenitor cells are produced in the conceptus. Runx1 is expressed in endothelial cells, mesenchymal cells, and in intra-aortic hematopoietic clusters, and in all committed hematopoietic progenitors and transplantable stem cells. We hypothesize that Runx1-CBFbeta is required, at least in part, for the transition between "hemogenic endothelium" and hematopoietic cells during fetal development. However, if Runx1 is deleted in adult mice, after hematopoiesis is established, long-term repopulating hematopoietic stem cells persist, committed erythroid, myeloid, and megakaryocytic progenitors increase in number, and both erythropoiesis and terminal granulocyte differentiation are normal. Thus, there is an absolute requirement for Runx1-CBFbeta to establish hematopoiesis in the fetus, but not to maintain all aspects of it in the adult. One of our goals is to define the developmental window and cell types in which Runx1-CBFbeta is required to specify definitive hematopoiesis in the conceptus. A second aim follows up on recent findings that the placenta may be a source of hematopoietic stem cells. We will determine where in the placenta hematopoietic stem cells reside, and whether they differentiate from endothelial cells in the allantois or in the placental labyrinth. Finally, we will attempt to identify the signaling sources that induce the first wave of Runx1 expression and definitive hematopoiesis in the conceptus. We will specifically examine whether Hedgehog, the upstream component of a signaling cascade required for definitive hematopoiesis in zebrafish, activates Runx1 expression and definitive hematopoiesis in the mouse conceptus. Together these aims will contribute to our understanding of the earliest events that establish definitive hematopoiesis in the mouse conceptus, and should help guide efforts to produce blood cells from embryonic sources in vitro.