Role of T-box genes in mouse development

描述（申请人提供）：项目描述。该项目的长期目标是了解转录因子基因T-box家族的发育作用。Tbx 4的突变导致早期致死，这是由于尿囊不能与绒毛膜融合并经历血管重塑。我们认为Tbx 4是Notch信号通路的上游，在血管发生中控制内皮细胞和周细胞（血管的支持细胞）之间的细胞命运决定。此外，我们发现了Tbx 4在造血中的作用，因为在绒毛尿囊胎盘建立后缺乏Tbx 4的条件突变体死于贫血。我们将检验Tbx 4对于胎盘迷路中造血干细胞（HSC）的分化和/或维持是必需的这一假设。Tbx 2、Tbx 3和Tbx 20纯合突变体都在妊娠期间由于心脏的明显缺陷而死亡。这些基因的表达结构域部分重叠，导致共享功能的可能性。我们发现了Tbx 2和Tbx 3之间的遗传相互作用，影响出生后的生存能力，这可能是由于心脏发育中的遗传相互作用。我们将使用我们现有的突变来探索心脏中的T-box基因相互作用。在Tbx 3中产生条件等位基因将促进这一奋进，并使我们能够进一步研究Tbx 3在后期发育中的作用。具体目的1：检验Tbx 4是尿囊中血管发生中Notch信号传导的上游的假设。具体目标二：检验Tbx 4对于胎盘造血是必需的并且胎盘来源的造血干细胞接种胎肝的假设。具体目标3：探索心脏发育中的T-box基因相互作用。具体目标4：产生Tbx 3的条件等位基因，以检查该基因在心脏和乳腺中的作用。相关性：T-box基因是许多发育过程的核心。胎盘造血的发现和迷路中HSC的胎盘生态位指出了Tbx 4具有重要作用的胎儿造血的新位点。我们提出的研究与理解造血系统的干细胞生物学有关。先天性心脏病（CHD）是人类最常见的出生缺陷，也是生命第一年死亡的主要原因。T-box转录因子与心脏发育密切相关，我们现有的突变提供了一个独特的机会来解开正常心脏发育的分子机制，并确定不同T-box基因的重叠功能作用。

DESCRIPTION (provided by applicant): Project Description. The long-term objective of this project is to understand the developmental roles of the T-box family of transcription factor genes. Mutation of Tbx4 results in early lethality due to failure of the allantois to fuse with the chorion and undergo vascular remodeling. We propose thatTbx4 is upstream of the Notch signaling pathway in vasculogenesis, controlling a cell fate decision between endothelial cells and pericytes, the supporting cells of blood vessels. In addition we have discovered a role for Tbx4 in hematopoiesis, as conditional mutants lacking Tbx4 after the establishment of the chorioallantoic placenta die of anemia. We will test the hypothesis that Tbx4 is essential for the differentiation and/or maintenance of hematopoietic stem cells (HSC) in the placental labyrinth. Tbx2, Tbx3 and Tbx20 homozygous mutants all die during gestation due to distinct defects in the heart. The expression domains of these genes are partially overlapping leading to the possibility of shared functions. We have uncovered a genetic interaction between Tbx2 and Tbx3 affecting postnatal viability that is likely due to genetic interaction in heart development. We will use mutations we have available to explore T-box gene interactions in the heart. The production of a conditional allele in Tbx3 will facilitate this endeavor and allow us to further investigate the role of Tbx3 in later development. Specific Aim 1: Test the hypothesis that Tbx4 is upstream of Notch signaling in vasculogenesis in the allantois. Specific Aim 2: Test the hypothesis that Tbx4 is essential for placental hematopoiesis and that placentally- derived hematopoietic stem cells seed the fetal liver. Specific Aim 3: Explore T-box gene interactions in heart development. Specific Aim 4: Produce a conditional allele of Tbx3 to examine the role of this gene in the heart and mammary gland. Relevance: T-box genes are central to many developmental processes. The discovery of placental hematopoiesis and the placental niche for HSC in the labyrinth point to a new site for fetal hematopoiesis with an important role for Tbx4. Our proposed studies have relevance to understanding stem cell biology of the hematpoietic system. Congenital heart defects (CHD) are the most common birth defects in humans and a leading cause of death in the first year of life. T-box transcription factors are critically involved in heart development and the mutations we have available provide a unique opportunity to unravel the molecular mechanisms underlying normal heart development and to identify overlapping functional roles of different T-box genes.