The p53 protein can bind to a set of specific DNA sequences, and this may activate the transcription of genes adjacent to these DNA elements. The mdm-2 gene is shown here to contain a p53 DNA-binding site and a genetically responsive element such that expression of the mdm-2 gene can be regulated by the level of wild-type p53 protein. The mdm-2 protein, in turn, can complex with p53 and decrease its ability to act as a positive transcription factor at the mdm-2 gene-responsive element. In this way, the mdm-2 gene is autoregulated. The p53 protein regulates the mdm-2 gene at the level of transcription, and the mdm-2 protein regulates the p53 protein at the level of its activity. This creates a feedback loop that regulates both the activity of the p53 protein and the expression of the mdm-2 gene.[Key Words: p53 protein; mdm-2 gene; autoregulatory feedback loop]
cells. Once transformed, the mesenchymal cells prolifer-1 Departments of Pathology and Developmental ate and invade the cardiac jelly, a basement membrane-Biology like substance elaborated by the myocardial cells. A Howard Hughes Medical Institute second process, which is even less well understood, 2 Cardiovascular Division begins after EMT. The endocardial cushion area elon-Department of Medicine gates and undergoes continuous remodeling that even-Stanford University Medical School tually refines the primitive cushion into thin elongated Stanford, California 94305 valve leaflets. Several signaling pathways have been implicated in heart valve morphogenesis. Studies with neutralizing Summary antibodies and antisense RNA indicate that TGF- signaling is essential for EMT in the chick (Eisenberg and The delicate leaflets that make up vertebrate heart Markwald, 1995; Nakajima et al., 2000). However, probavalves are essential for our moment-to-moment exisbly due to functional redundancy in the mammalian systence. Abnormalities of valve formation are the most tem, mice with single mutations in the TGF- family common serious human congenital defect. Despite members or their receptors do not have impaired EMT. their importance, relatively little is known about valve The Wnt/-catenin pathway is essential for EMT in zedevelopment. We show that the initiation of heart valve brafish (Hurlstone et al., 2003). In mice, however, Wnt morphogenesis in mice requires calcineurin/NFAT to plays an essential early role in cardiac myogenesis repress VEGF expression in the myocardium underly-(Olson and Schneider, 2003), thus obscuring any later ing the site of prospective valve formation. This represroles in heart valve formation. Also, Notch signaling has sion of VEGF at E9 is essential for endocardial cells recently been shown to promote EMT in mice (Timmerto transform into mesenchymal cells. Later, at E11, a man et al., 2004). EGF-related growth factors and their second wave of calcineurin/NFAT signaling is required receptors are important in regulating heart valve formain the endocardium, adjacent to the earlier myocardial tion in mice. Loss of endocardial HB-EGF or EGFR resite of NFAT action, to direct valvular elongation and sults in abnormal hyperplasia of cushion mesenchymal refinement. Thus, NFAT signaling functions sequencells (Chen et al., 2000; Iwamoto et al., 2003; Jackson tially from myocardium to endocardium within a valvuet al., 2003). Lack of endocardial neuregulin-1 or cushion lar morphogenetic field to initiate and perpetuate mesenchymal ErbB3 results in severe mesenchymal hyembryonic valve formation. This mechanism also oppoplasia in the cushion area (Camenisch et al., 2002; erates in zebrafish, indicating a conserved role for Erickson et al., 1997; Meyer and Birchmeier, 1995). Ras calcineurin/NFAT signaling in vertebrate heart valve signaling is also crucial for cushion mesenchymal develmorphogenesis. opment. Loss of endothelial neurofibromin-1, which inactivates Ras, results in hyperplasia of cushion mesen-
Developing myocardial cells respond to signals from the endocardial layer to form a network of trabeculae that characterize the ventricles of the vertebrate heart. Abnormal myocardial trabeculation results in specific cardiomyopathies in humans and yet trabecular development is poorly understood. We show that trabeculation requires Brg1, a chromatin remodeling protein, to repress ADAMTS1 expression in the endocardium that overlies the developing trabeculae. Repression of ADAMTS1, a secreted matrix metalloproteinase, allows the establishment of an extracellular environment in the cardiac jelly that supports trabecular growth. Later during embryogenesis, ADAMTS1 expression initiates in the endocardium to degrade the cardiac jelly and prevent excessive trabeculation. Thus, the composition of cardiac jelly essential for myocardial morphogenesis is dynamically controlled by ADAMTS1 and its chromatin-based transcriptional regulation. Modification of the intervening microenvironment provides a mechanism by which chromatin regulation within one tissue layer coordinates the morphogenesis of an adjacent layer.
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