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T-box转录因子基因家族的发育作用。Tbx4的突变导致早期死亡，原因是尿囊膜未能与绒毛膜融合并经历血管重塑。我们认为Tbx4是血管生成中Notch信号通路的上游，控制着内皮细胞和周细胞之间的细胞命运决定，周细胞是血管的支持细胞。此外，我们还发现了Tbx4在造血中的作用，因为在绒毛尿囊膜胎盘建立后缺乏Tbx4的条件突变体死于贫血。我们将验证Tbx4对胎盘迷路中的造血干细胞(HSC)的分化和/或维持至关重要的假设。Tbx2、Tbx3和Tbx20纯合子突变体都会在怀孕期间死于明显的心脏缺陷。这些基因的表达结构域部分重叠，导致了共享功能的可能性。我们已经发现Tbx2和Tbx3之间的遗传交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交互作用。我们将使用现有的突变来探索心脏中T-box基因的相互作用。TBX3中条件等位基因的产生将促进这一努力，并使我们能够进一步研究TBX3在以后发育中的作用。具体目标1：验证Tbx4是Notch信号的上游在尿囊膜血管生成中的假设。具体目标2：验证Tbx4对胎盘造血和胎盘来源的造血干细胞是胎肝种子的假设。具体目标3：探索心脏发育过程中T-box基因的相互作用。特定目的4：产生条件等位基因TBX3，以检测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。胎盘造血和HSC在迷路中胎盘生态位的发现为胎儿造血提供了一个新的部位，其中Tbx4起着重要的作用。我们提出的研究对于理解造血系统的干细胞生物学具有重要意义。先天性心脏病(CHD)是人类最常见的出生缺陷，也是导致出生第一年死亡的主要原因。T-box转录因子在心脏发育过程中起着至关重要的作用，我们所获得的突变为揭示心脏正常发育的分子机制和确定不同T-box基因的重叠功能提供了一个独特的机会。

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.