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.
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