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The Role of Notch in the Control of Fetal Heart Development and Adult Heart Function
The Notch family of transmembrane receptors mediate many cell fate decisions during embryonic development. Depending on other signals, Notch can regulate asymmetric division of a stem or progenitor cell, select between alternate fates within a field, or establish a boundary between cells. Notch signaling is activated by two classes of transmembrane ligands, Jagged/Serrate and Delta families, that are commonly located on adjacent cells. In the early heart field, we showed that Notch suppresses myocardial differentiation and permits cells to develop into non-muscle mesocardium and pericardial roof (Rones et al.). Suppression of myocardial fate by Notch is seen not only in vertebrates, but in Drosophila as well; thus, we believe Notch to be an evolutionarily conserved mechanism to regulate the size or number of myocardial cells during early heart formation. At later stages of heart development, Notch establishes the atrioventricular canal as distinct from atrial and ventricular chamber myocardium (Rutenberg et al.). In humans, attenuated Notch signaling underlies Alagille syndrome, which includes congenital heart defects such as outflow tract defects and valvuloseptal anomalies that are likely to result from mispatterning of this region as the heart develops. Notch initiates a genetic cascade that involves bone morphogenetic factor 2 (BMP2) and T-box transcription factors. Our current interest is understanding how Notch controls the pool of cardiomyocyte progenitors, both during fetal development and potentially in the adult, as well as the involvement of Notch in cardiomyocyte homeostasis in the adult. Notch controls cell cycle entry of immature cardiomyocytes (Campa et al., 2008). As part of an NHLBI-sponsored program, we are studying the implications of Notch signaling for adult heart function and regeneration. We have created transgenic mouse adult conditional myocardial knockouts of Notch function and are now evaluating the response of these animals to surgical models of myocardial infarct and chronic overload.
People Victor M. Campa, PhD, postdoctoral fellow Fabio Cerignoli, PhD, postdoctoral fellow Brandon Nelson, MS, Manager, Burnham hESC Laboratory Maria Cecilia Scimia, MD, CIRM clinical fellow Ramón Trelles Diaz, PhD, postdoctoral fellow
Recent Publications Campa, V.M., Gutiérrez-Lanza, R., Diaz-Trelles, R., Cerignoli, F., Tsuji, T., Jiang, W., and Mercola, M. (2008). Notch Activates Cell Cycle Re-entry and Progression in Postmitotic Cardiomyocytes. In press. Rutenberg, J. B., Fischer, A., Jia, H., Gessler, M., Zhong, T. P. and Mercola, M. (2006). Developmental patterning of the cardiac atrioven- tricular canal by Notch and Hairy-related transcription factors. Development 133, 4381-90. [Pubmed]Rones, M. S., Woda, J., Mercola, M. and McLaughlin, K. A. (2002). Isolation and characterization of Xenopus Hey-1: A downstream mediator of Notch signaling. Dev Dyn 225, 554-60. [Pubmed] Rones, M. S., McLaughlin, K. A., Raffin, M. and Mercola, M. (2000). Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis. Development 127, 3865-76. [Pubmed] McLaughlin, K. A., Rones, M. S. and Mercola, M. (2000). Notch regulates duct cell fate in the developing pronephros. Developmental Biology 227, 567-80. [Pubmed]
Funding NIH Heart, Lung and Blood Institute
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