During the midgestation of mammalian embryonic development (E9.5-E15.5), the newly formed embryonic heart is required to grow rapidly in cell number and size and undergoes a series of morphological and functional changes in response to the increasing volume of circulating blood. The proliferating cardiomyocytes form a distinct loose interwoven meshwork of myocardial fibers, the so-called ventricular trabeculae, in E9.5 ventricular chambers. By E14.5, these trabecular structures become more compact toward the epicardial surface, and the intertrabecular recesses are reduced to capillaries. The significant reduction of trabeculation is closely associated with the myocardium growth arrest that leads to an early embryonic lethality. On the other hand, the abnormal enhancement of growth activity of myocardium leads to the failure of myocardial compaction, which is likely the cause of a severe pediatric cardiac disease, Noncompaction of the Ventricular Myocardium, in humans. However, there is little known about the underlying molecular and cellular mechanism. Recently, we found that a member of transforming growth factor beta superfamily, Bone Morphogenetic Protein-10 (BMP10), may be a novel peptide growth factor involved in the cardiac ventricular trabeculation and compaction during the midgestation stages. This proposal is designed to test our hypothesis that BMP-l0 is critical to the cardiac growth and ventricular trabeculation-compaction using both in vitro and in vivo analyses. We propose to: 1) Assess the role of BMP-10 in enhancing embryonic cardiomyocyte proliferation using two cardiomyocyte growth assays in vitro; 2) Determine the BMP-10 dependency of cardiomyocyte proliferation; 3) Analyze the role of BMP-10 in cardiac development by generating BMP-10- deficient mice; 4) Further define the role of BMP-10 using a transgenic approach. We believe that our effort will shed light on further understanding of cardiac development and some forms of congenital cardiac defects.
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