Professor Richard Harvey, PhD, FAAHead, Developmental Biology DivisionDeputy Director, Victor Chang Cardiac Research Institute Sir Peter Finley Professor of Cardiac Research, University of New South Wales
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The heart is the first organ to function in the mammalian embryo and is highly susceptible to genetic pertubrations leading to congenital malformations. The heart is beautiful in form, efficient in function and intricate in regulation. Understand the molecular basis of embryo patterning and organogenesis, the relationships between organ form and function, and the logic and evolution of regulatory networks, presents great challenges for the developmental biologist. Our laboratory studies the developmental and molecular mechanisms that guide lineage specification, morphogenesis and adaptation in the mammalian heart, and how these mechanisms relate to congenital heart disease.
We principally use the mouse as a mammalian model although have also worked in fruitflies, frogs, and other systems according to their strengths in unravelling molecular mechanisms. Over the years we have worked extensively with gene targeting technology in mice, refining our ability to probe the genetic basis of development in a time and tissue-dependent manner. Genetic technologies are becoming more sophisticated and genomics and bioinformatics are having a major impact on how we handle and deal with biological information. A key focus is the transcription factors that regulate cardiogenesis and we are progressing towards a systems biology-level of appreciation of regulatory pathways. We have isolated and studied novel mouse genes of the homeobox and T-box families, and have demonstrated their essential role in formation and patterning of the heart in the embryo.
It is becoming increasingly evident that many congenital malformation of the heart, which are very common in babies, can be traced back to the very earliest stages of heart development, arising as behavioural defects in stem and progenitor cell populations in the embryo. Understanding the connections between congenital heart malformations and embryonic mechanisms is one of our key goals, and we are committed to the notion that simple treatments may eventually be found that render the regulatory pathways of the heart more robust to genetic or environmenal insult.
Recently we have begun to explore the biology of endogenous cardiac stem cells and the prospects for endogenous regeneration in heart disease. The stem cell field hasrevitalised developmental biology and we are in turn attempting to bring the tools and perspectives of developmental biology to our study of adult stem cells and regeneration. This is an exciting time to be a biologist and our program attempts to make our explorations of the early embryo relevant to adult human biology.
Postdoctoral Fellows
Orit Wolstein, PhD
Romaric Bouveret, PhD
Vashetharan Chandrakanthan, PhD
Munira Xaymarden, BDS, MMS, PhD
Naisana Asli, PhD
Stella Lee, PhD
Danielle de Jong, PhD
Amita Limaye, PhD
Bioinformatician
Tram Doan, M. Mol Biotech
PhD Students
James Chong, MBBS
Mahdi Moradi Marjaneh, MD
Research Assistants
Sue Ku M. Sc
Other
Helena Malinowska (Honours Student)
Shanthosh Sivapathan (Independent Student)
Recent Publications:
Christoffels VM, Habets PEMH, Franco D, Campione M, de Jong F, Lamers WH, Bao Z-Z, Palmer S, Biben C, Harvey RP, Morman AFM. Chamber formation and morphogenesis in the developing mammalian heart. Developmental Biology 2000; 223:266-278
Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Barnett L, Koentgen F, Robb L, Feneley M, Harvey RP. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circulation Research 2000; 87:888-895
Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay J, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that posulates cardiac development. Cell 2002; 110:713-2
Elliot DA, Kirk E, Yeoh T, Chander S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. Journal of the American College of Cardiology 2003; 41:2072-76
Von Both I, Silvestri C, Erdemir T, Lickert H, Walls JR, Henkelman RM, Rossant J, Harvey RP, Attisano L, Wrana JL. Foxh1 is essential for development of the anterior heart field. Developmental Cell 2004; 7:331-45
Stennard FA, Costa MW, Lai D, Biben C, Furtado MB, Solloway MJ, McCulley DJ, Leimena C, Preis JI, Dunwoodie SL, Elliot DE, Prall OWJ, Black BL, Fatkin D, Harvey RP. Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. Development 2005; 132:2451-462
Elliot DA, Solloway MJ, Wise N, Biben C, Costa M, Furtado MB, Lange M, Dunwoodie S, Harvey RP. A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery. Development 2006; 133:133-22
Kirk EP, Hyan C, Martin ICA, Biben C, Thomson PC, Buckley MF, Moran C, Harvey RP. Quantitative trait loci modifying cardiac atrial septal morphology and risk of patent foramen ovale in the mouse. Circulation Research 2006; 98:651-58
Christoffels VM, Mommersteeg MTM, Trowe M-o, Prall OWJ, de Gier-de Vries C, Soufan AT, Bussen M, Schuster-Gossler K, Harvey RP, Moorman AFM, Kispert A. Formation of the venous pole of the heart from an Nkx2-5-negative cell population requires Tbx18. Circulation Research 2006; 98:1555-63
Mommersteeg MTM, Hoogaars WMH, Prall OWJ, de Gier-de Vries C, Wiese C, Papaioannou VE, Brown NA, Harvey RP, Moorman AFM, Christoffels VM. Molecular pathway for the localized formation of the sinoatrial node. Circulation Research 2007; 100:354-62
Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro MK, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS, Harvey RP. Mutations in cardiac T-box factor TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis, and cardiomyopathy. American Journal of Human Genetics 2007; 81:280-291.
Prall OWJ, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H, Stennard FA, Wise N, Schaft D, Wolstein O, Furtado MB, Shiratori H, Hamada H, Black BL, Saga Y, Robertson EJ, Buckingham ME, Harvey RP. A Nkx2-5/Bmp2/Smad1 negative feedback loop orchestrates cardiac progenitor cell specification and proliferation in the second heart field. Cell 2007; 128:947-59
Siero F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martinez-A, Mackay CR, Mackay F. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proceeding of the National Academy of Science (USA) 2007: 104:14759-764.
Yadava RS, Frenzel I?I, McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thorton CA, Prall OWJ, Harvey RP, Mahadeven MS. RNA toxicity in mytonic muscular dystrophy induces NKX2-5 expression. Nature Genetics 2008; 40:61-68.
Drenckhahn J-D, Schwarz QP, Gray S, Laskowski A, Kiriazis H, Ming Z, Harvey RP, Du X-J, Thornburg DR, Cox TC. Compensatory growth of healthy cardiac cells in the presence of diseased cells restores cardiac tissue homeostasis during heart development. Developmental Cell [in press 03.09.08]
Furtado MB, Solloway MJ, Jones V, Costa MW, Biben C, Wolstein O, Preis JI, Sparrow DB, Saga Y, Dunwoodie SL, Robertson EJ, Tam PPL, Harvey RP. BMP/SMAD1 signalling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4. Genes and Development [in press 08.09.08]
Posch MG, Gramlich M, Sunde M, Schmitt K, Richter S, Perrot A, Panek AN, Al Khatib I, Nemer G, Megarbane A, Dietz R, Stiller B, Berger F, Harvey RP, Ozcelik C. A Gain-of-function TBX20 Mutation Causes Congenital Atrial Septal Defects, Patent Foramen Ovale and Cardiac Valve Defects. Journal of Medical Genetics 2009 Sep 16.
Xaymardan M, Cimini M, Fazel S, Weisel RD, Lu WY, Martin U, Harvey RP, Li RK. c-Kit function is necessary for in vitro myogenic differentiation of bone marrow hematopoietic cells. Stem Cells 2009;27(8):1911-20.
Esposito G, Grutter G, Drago F, Costa MW, De Santis A, Bosco G, Marino B, Bellacchio E, Lepri F, Harvey RP, Sarkozy A, Dallapiccola B. Molecular analysis of PRKAG2, LAMP2, and NKX2-5 genes in a cohort of 125 patients with accessory atrioventricular connection. American Journal of Medical Genetics A 2009;149A(7):1574-7.
Macindoe I, Glockner L, Vukasin P, Stennard FA, Costa MW, Harvey RP, Mackay JP, Sunde M. Conformational stability and DNA binding specificity of the cardiac T-box transcription factor Tbx20. Journal of Molecular Biology 2009;389(3):606-18.
Ferdous A, Caprioli A, Iacovino M, Martin CM, Morris J, Richardson JA, Latif S, Hammer RE, Harvey RP, Olson EN, Kyba M, Garry DJ. Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo. Proceedings of the National Academy of Science (USA) 2009;106(3):814-9.
Reviews:
Harvey RP. Patterning the vertebrate heart. Nature Reviews Genetics 2002; 3:544-56
Stennard F, Harvey RP. T-box transcription factors and their roles in regulatory hierarchies in the developing heart. Development 2005: 132:4897-910
Trounsen A, Harvey RP. ?A critical time for stem cell research in Australia? Cell Stem Cell 2008; 2:1-5
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