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Big, Bad Hearts: from Flies to Man

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Big, Bad Hearts: from Flies to Man COMMENTARY Big, bad hearts: From flies to man Fabrizio C. Serluca and Mark C. Fishman* Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 enetic screens have revealed sponsible gene is unknown, so it would important molecular pathways related essential genes that guide be very useful to have a compendium of to contractility are shared and, as Wolf metazoan complexity, from candidate genes. That is what a model et al. (4) demonstrate, that mutations of fates of individual cells, to system might offer. sarcomeric proteins do lead to dimin- Gpatterning of cell arrays, to their assem- ished contractile function and cardiac bly into organs (1–3). Genetic Screens for Physiology? enlargement. Now the Ur-genetic organism Dro- One vertebrate species, the zebrafish, Of course, the physiology of the hu- sophila is making a play to provide has already been subject to screens for man heart differs in many regards genes for a next wave of biology: heart mutations, including those that from that of Drosophila. The Drosoph- integrative physiology. How do organs interfere with contractility (3). One ila heart is a tube, lacking endothe- move, beat, digest, secrete, behave, and advantage of the zebrafish embryo is lium, composed of two thin layers of interact in manners adjusted to changing its transparency, so contractility can be muscle oriented in the circumferential needs of an organism? How can such monitored visually. In that species, mu- and longitudinal directions (11). Con- features be monitored without perturb- tations in sarcomeric proteins and tractions squeeze along the tube and ing the very processes under study? novel signaling pathways have been drive perilymph in alternating direc- In a recent issue of PNAS, Wolf et al. discovered to perturb contractility (6, tions, as pacemakers alternate between (4) chose heart contractility as the phys- 7). Although not as readily subject to anterior and posterior heart (12). The iological target. They monitored and large-scale genetic screens, mouse low pressure generated suffices for an quantitated how well the beating heart heart function can be assessed nonin- open circulation, in which the vascular of an adult fly empties on each beat and vasively as well, and contractility can fluid (perilymph) percolates around did so noninvasively, using optical co- be demonstrably affected, for example, the tissues before returning to the herence tomography (OCT), a technique by mutation in laminin-␣4 (8). heart. In contrast, the thick-walled that creates an image of the sample by muscular human heart must perfuse a analyzing its interference pattern of a much larger body at high pressure and broadband light source emission. They Much of the does so through a closed circulation. showed that contractility declines and The human heart has four distinctive that the heart enlarges when the cardiac cellular machinery of chambers, separated from each other myocytes bear mutations in the sarco- by valves to ensure unidirectional flow. meric or cytoskeletal proteins troponin heart cells is the same A single pacemaker node sets the heart I, tropomyosin 2, or ␦-sarcoglycan. They rate, and ramifications of specialized proposed that this is a useful model between Drosophila conduction tissue throughout the heart to discover genes responsible for the ensure that chambers beat in a syn- human disorder cardiomyopathy. and humans. chronous and coordinated fashion. The heart and vessels are lined by endothe- Cardiomyopathy lium, which is a key element during Cardiomyopathies are primary disorders The big advantage of Drosophila is embryological development and subse- of heart muscle [by convention not in- the ease of large-scale screens combined quently helps to ensure fluidity of the cluding those due to high blood pres- with the ready recovery of causal muta- blood. In addition, the physiology of sure, due to congenital disease, or after tions, using inserted transposons as tags. the human heart is embedded in an heart attacks (5)]. The most prevalent In addition, genetic pathways can be integrated mammalian physiological form in the U.S. is dilated cardiomyopa- assembled in Drosophila by using sensiti- system designed to maintain tissue oxy- thy, when the heart gets bigger because zation screens, where the tuning down genation through all types of weather. of chamber enlargement, most especially of one gene is used to reveal interacting Contractility increases to maintain car- the left ventricle. The essential physio- roles of a second. diac output in the face of threat or logical problem is diminished contractil- hemorrhage, a homeostatic response Heart Evolution ity, which, as it progresses, generally coordinated by complex interplay of leads to symptoms of heart failure and So how much resemblance does the hormones released from the kidney, Ͼ death, with 10% dying annually (5). heart of Drosophila bear to that of the the adrenal, the heart, and the brain. Not all big hearts are bad hearts. Ath- human, and how reasonable a model Further studies will be needed to letes often have enlarged ventricles that can it provide of the dilated cardio- see to what degree the failing fly contract perfectly normally. myopathies? Much of the cellular heart resembles the human heart. For Alcohol and other toxins can cause machinery of heart cells is the same example, it is not known whether the cardiomyopathy, but, in the majority of between these species, even though they fly heart contractility normally in- cases, the etiology is unknown. Interest- are presumed to have diverged at the creases with dilation, an important ingly, in more than a quarter of these invertebrate–vertebrate junction Ͼ500 ‘‘idiopathic’’ cases, the cardiomyopathy million years ago (Mya) and may have is familial, suggesting genetic predisposi- arrived at their hearts by convergent Conflict of interest statement: No conflicts declared. tion. Mutations leading to dilated car- evolution not from a shared ancestral See companion article on page 1394 in issue 5 of volume diomyopathy have been identified in heart. Orthologous genes direct cardiac 103. proteins of the sarcomere, cytoskeleton, cell fate decisions (e.g., nkx 2.5) and the *To whom correspondence should be addressed. E-mail: basement membrane, and calcium regu- generation of the contractile sarcomeres mark.fi[email protected]. latory systems. In many cases, the re- (9, 10). It is reasonable to presume that © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0600900103 PNAS ͉ March 14, 2006 ͉ vol. 103 ͉ no. 11 ͉ 3947–3948 Downloaded by guest on September 28, 2021 compensatory element for the human, do not detract from the importance of sive components of pathways, perhaps or how it responds pathologically to doing a screen in Drosophila for con- with nodes amenable to therapeutic injury. Is there, as in the human with tractility mutations, using the elegant pharmaceutical intervention. these diseases, fibrosis accompanied system established by Wolf et al. (4). These studies are yet more proof of by cellular hypertrophy and atrophy, Cellular defects in contractile and cy- the power of genetics to reveal the processes believed to represent activa- toskeletal machinery certainly form the function of key genes in the intact ani- tion of pathological signaling path- bulk of defined cardiomyopathy muta- mal and to help to identify key func- ways, themselves contributing to the tions. New mutations may point directly tional elements, in this case at the dysfunction (5)? to genes that are novel candidates for level of organ physiology, that most The obvious discrepancies between human cardiomyopathy or, through sen- integrative and clinically relevant of hearts separated at the late Precambrian sitization screens, identify otherwise elu- sciences. 1. Ellis, H. M. & Horvitz, H. R. (1986) Cell 44, 817–829. 5. Zipes, D. O., Libby, P., Bonow, R. O. & Braun- Ross, J., Jr., Tryggvason, K., et al. (2006) J. Biol. 2. Nu¨sslein-Volhard, C. & Wieschaus, E. (1980) wald, E. (2005) Braunwald’s Heart Disease Chem. 281, 213–220. Nature 287, 795–801. (Elsevier Saunders, New York). 9. Bodmer, R. (1993) Development (Cambridge, 3. Stainier, D. Y., Fouquet, B., Chen, J. N., Warren, 6. Mably, J. D., Mohideen, M. A., Burns, C. G., U.K.) 118, 719–729. K. S., Weinstein, B. M., Meiler, S. E., Mohideen, Chen, J. N. & Fishman, M. C. (2003) Curr. Biol. 13, 10. Lyons, I., Parsons, L. M., Hartley, L., Li, R., M. A., Neuhauss, S. C., Solnica-Krezel, L., Schier, 2138–2147. Andrews, J. E., Robb, L. & Harvey, R. P. (1995) A. F., et al. (1996) Development (Cambridge, U.K.) 7. Xu, X., Meiler, S. E., Zhong, T. P., Mohideen, M., Genes Dev. 9, 1654–1666. 123, 285–292. Crossley, D. A., Burggren, W. W. & Fishman, 11. Demerec, M. (1994) Biology of Drosophila (Cold 4. Wolf, M. J., Amrein, H., Izatt, J. A., Choma, M. A., M. C. (2002) Nat. Genet. 30, 205–209. Spring Harbor Lab. Press, Woodbury, NY). Reedy, M. C. & Rockman, H. A. (2006) Proc. Natl. 8. Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, 12. Dulcis, D. & Levine, R. B. (2005) J. Neurosci. 25, Acad. Sci. USA 103, 1394–1399. A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., 271–280. 3948 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0600900103 Serluca and Fishman Downloaded by guest on September 28, 2021.
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