FUNCTION OF FOREGUT ENDODERM IN CARDIOGENSIS

据估计，心血管畸形导致美国1%的儿童出生缺陷，死胎数量是10倍。 导致先天性心肌病的主要遗传缺陷大多不清楚。 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胚胎发育期间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/后轴沿着形成图案，导致腔室特异性基因表达的程序. 心肌起源于中胚层，因此最近的分子遗传学分析集中在心源性中胚层的调控和发育上。 然而，胚胎学和最近的遗传实验表明，内胚层也发挥着重要的功能，在调节心脏发生，虽然分子和生理基础是未知的。 目前的数据是一致的假设，推定和发展的前肠内胚层，调节类维生素A信号下游的加塔转录因子，是正确的心管图案和形态发生的关键。 我们建议使用一种新的维生素A缺乏鹌鹑模型来验证这一假设，使用移植实验和逆转录病毒表达技术。 我们将测试候选的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使用分化加塔-4缺陷小鼠ES细胞鉴定的基因。 预计内胚层发育的保守遗传组分将被鉴定为与心管形态发生相关。 具体目标是：1.确定类维生素A信号是否需要在前肠早期心管形态发生。 2.确定加塔因子表达是否足以在缺乏类维生素A信号传导的情况下挽救前肠发育和早期心管形态发生。 3.鉴定与心管形态发生相关的前肠内胚层中表达的加塔因子靶标。

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.