Converging Pathways and Principles in Heart Development and Disease CV@CSH

pace, forging unsuspected connections with human cardiovascular physiology and disease. The translucent nature of the organism has facilitated large scale mutagenesis screens for diverse cardiovascular phenotypes (for a review, see Shin and Fishman, 2002), while the density Kenneth R. Chien1,3 and Eric N. Olson2,3 Institute of Molecular Medicine University of California, San Diego, School of Medicine La Jolla, California 92093 2 Department of Molecular Biology of the zebrafish genetic map and ongoing genome projThe University of Texas Southwestern ect have led to an ability to clone the corresponding Medical School genes within a relatively short time span (3–6 months). Dallas, Texas 75390 The system appears to be particularly valuable for identifying new genes and pathways in vasculogenesis. gridlock, a gene that encodes a member of the Hairy/ “One country, two systems.” —Deng Xiaoping, referring to the reunification of Hong Enhancer of Split family of related bHLH proteins, acts Kong and China. as a molecular switch for the distinct identity of arteries New York Times, January 2, 1985 and veins by repressing the venous cell fate in pre-angioblasts, which is thereby permissive for artery formation. As noted by a former Chairman, the term “one countryThe zebrafish mutant phenotype resembles aspects of two systems” was initially coined to describe a new human aortic coarctation (Zhong et al., 2001). The ability experimental paradigm for normalized relations beof gridlock to govern the decision between arterial and tween Hong Kong and China, two territories that had venous cell fates is a reflection of its activity as a tranlong been united, but had evolved along separate paths scriptional target of the Notch signaling pathway, long during the Twentieth Century. Over the past 50 years, known to dictate mutually exclusive cell fates in diverse studies of the cardiovascular system have also evolved cell types. Surprisingly, knockout mice for the gridlock along distinct pathways, largely based upon the territoortholog Hey2 do not show aortic coarctation, but frerial boundaries of modern developmental biology and quently succumb to severe neonatal cardiomyopathy. clinical physiology. The developmental viewpoint has A combined loss of Hey1 and Hey2, however, leads been underpinned by genetics, and a reductionist apto vascular defects similar to gridlock, suggesting that proach toward mechanism, with molecular biology as these genes have undergone partial subor neofuncits primary tool, and the smallest biological unit being tionalization during vertebrate evolution (M. Gessler, individual cell types. The clinical cardiology viewpoint University of Wuerzburg). has been based on physiology, and an integrative apTwo new genes that lie in an identical pathway for the proach toward mechanism, with interventional/device/ endothelial-myocardial driven cues for valvulogenesis imaging technologies as the primary tools, and the (Walsh and Stainier, 2001) (D. Stainier, UCSF) were presmallest biological unit being the intact organ. In short, sented, as well as a new transgenic strain harboring a studies of the cardiovascular system have traditionally fli-1 GFP construct that allows in vivo visualization of been approached by citizens of “two” very different scithe entire vasculature. This strain should facilitate subentific cultures and “countries,” each with their own sequent modifier screens utilizing existing mutants with societies, uniforms, icons, and customs. If the recent interesting vascular phenotypes (Weinstein, NIH). In this 67 Quantitative Symposium of Cold Spring Harbor Labregard, over 700 mutants that affect discrete steps of oratory on “The Cardiovascular System” is any guide, zebrafish vessel formation and/or maturation have been this era of “one system-two countries” is coming to a isolated (H. Habeck, Exelixis, Germany). Mark Fishman close. During this symposium, converging pathways and (MGH) presented an elegant case for the zebrafish as a perspectives of cardiovascular development and physisystem to unravel the “logic” of disease pathogenesis. ology were presented, driven by post-genomic tools and Toward this end, a compelling argument can be made technology, a new generation of scientists and physithat a parallel effort on physiological characterization of cians trained to work at the interface of developmental this model organism is now warranted to allow direct biology, genetics, physiology, and human disease, and connections between novel genes and clinically relevant an integrative approach to biology. This review highfunctional endpoints. Clearly, studies in zebrafish are lights some of the central themes presented by deledemonstrating that the border between developmental gates of both “countries” that provided new insights biology and disease is dissolving as shared pathways for into developmental principles of human cardiovascular prenatal morphogenic steps and postnatal physiological physiology and disease. events continue to be uncovered.