FUNCTION OF FOREGUT ENDODERM IN CARDIOGENSIS

据估计，心血管畸形在美国导致1%的儿童出生缺陷和10倍于此的死产。导致先天性心肌病的主要遗传缺陷大多还不清楚。然而，由于心脏发育涉及一系列复杂的组织运动、融合和重塑，在许多情况下，先天性心脏异常被认为是由于胚胎发育过程中的形态发生缺陷引起的。我们的长期目标是了解胚胎心管形态发生的转录调控。一个重要但知之甚少的过程是原始心管的形成，即沿着前后轴形成图案，导致特定于房间的基因表达程序。心肌来源于中胚层，因此最近的分子遗传学分析主要集中在心源性中胚层的调节和发育。然而，胚胎学和最近的遗传学实验表明，内胚层也在调节心脏发生中发挥重要作用，尽管其分子和生理基础尚不清楚。目前的数据与一种假设是一致的，即假定和发育的前肠内胚层，由视黄醇信号下游的GATA转录因子调节，对正确的心管构型和形态发生至关重要。我们建议通过移植实验和逆转录病毒表达技术，使用一种新的缺乏维生素A的鹌鹑模型来验证这一假说。我们将测试候选已知和新的内胚层表达基因的功能，包括那些在微阵列表达实验中确定的基因，使用分化GATA-4缺陷的小鼠ES细胞。预计内胚层发育的保守遗传成分将与心管形态发生相关。其具体目的是：1.确定前肠中是否需要维甲酸信号来促进心脏导管的早期形态发生。2.确定在缺乏维甲酸信号的情况下，GATA因子的表达是否足以挽救前肠发育和早期心管形态发生。3.筛选与心管形态发生相关的前肠内胚层表达的GATA因子靶点。

Cardiovascular malformations are estimated to cause in the US birth defects in 1 percent of children and 10 times as many stillbirths. The primary genetic defects leading to congenital cardiomyopathies are mostly not understood. However, because heart development involves a series of complex tissue movements, fusions, and remodelings, in many cases congenital cardiac abnormalities are thought to arise from defects in morphogenesis during embryonic development. Our long-term goal is to understand the transcriptional regulation of embryonic heart tube morphogenesis. An important but poorly understood process is the formation of the primitive heart tube, that is patterned, along the anterior/posterior axis, leading to programs of chamber- specific gene expression. The myocardium is derived from mesoderm, and recent molecular genetic analyses have therefore focused on the regulation and development of cardiogenic mesoderm. However, embryological and recent genetic experiments indicate that endoderm also plays an important function in regulating cardiogenesis, although the molecular and physiological basis is not known. Current data is consistent with a hypothesis that presumptive and developing foregut endoderm, regulated by GATA transcription factors downstream of retinoid signaling, is critical for proper heart tube patterning and morphogenesis. We propose to use a novel vitamin-A deficient quail model to test this hypothesis, using transplantation experiments and retroviral expression techniques. We will test the function of candidate known and novel endoderm-expressed genes, including those identified in micro-array expression experiments using differentiating GATA-4 deficient murine ES cells. It is anticipated that conserved genetic components of endoderm development will be identified with relevance to heart tube morphogenesis. The specific aims are to: 1. Determine if retinoid signaling is required in foregut for early heart tube morphogenesis. 2. Determine if GATA factor expression is sufficient to rescue foregut development and early heart tube morphogenesis in the absence of retinoid signaling. 3. Identify GATA factor targets expressed in foregut endoderm relevant to heart tube morphogenesis.