| Abstract
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During early embryogenesis, heart and skeletal muscle progenitor cells are thought to derive from distinct regions of the mesoderm (i.e. the lateral plate mesoderm and paraxial mesoderm, respectively). In this study, we have employed both in vitro and in vivo experimental systems in the avian embryo to explore how mesoderm progenitors in the head differentiate into both heart and skeletal muscles. We found that, in vitro, the head mesoderm can be regionalized into two separate populations: the cranial paraxial mesoderm and the splanchnic mesoderm which, in culture, undergo myogenesis and cardiogenesis, respectively. Using fate-mapping studies, gene expression analyses, and manipulation of signaling pathways in the chick embryo, we demonstrated in vivo that cells from the cranial paraxial mesoderm contribute to both myocardial and endocardial cell populations within the cardiac outflow tract. We further show that Bmp signaling affects the specification of mesoderm cells in the head: application of Bmp4, both in vitro and in vivo , induces cardiac differentiation in the cranial paraxial mesoderm and blocks the differentiation of skeletal muscle precursors in these cells. Our results demonstrated that a subset of cranial paraxial mesoderm cells is a novel source of cardiac progenitors in the cardiac outflow tract in vivo. These findings were published in Development (Tirosh-Finkel et al. 2006). The splanchnic mesoderm of the anterior heart field contributes to significant portions of the heart, including the outflow tract, the right ventricle and atria. These cells express distinct cardiac markers when grown in culture, yet rarely undergo final differentiation into beating cardiomyocytes. Administration of BMP4 induced beating of the SpM-derived cardiomyocytes, suggesting a positive role for Bmp signaling in the terminal differentiation of cardiac progenitors. In a subsequent project in my thesis we performed a large-scale microarray screen for genes whose expression is induced or reduced by BMP4. This screen revealed novel insights on the role of the Bmp signaling pathway in the differentiation of cardiomyocytes; BMP4 markedly elevated the expression of numerous sarcomeric proteins. In addition, we uncovered a tight crosstalk between the Bmp and Fgf signaling pathways in the SpM: BMP4 blocks Fgf signaling. We suggest that Bmp and Fgf signaling pathways are under tight spatiotemporal regulation, via their synexpression group members, to allow anterior heart field cells to differentiate at the right time and place. A deeper understanding of the mesodermal lineage specification in the vertebrate head is expected to provide insights into the normal, as well as pathological, aspects of heart and craniofacial development.
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