BBS Faculty Member - C. Geoffrey Burns

C. Geoffrey Burns

Department of Medicine

Harvard Medical School
149 13th Street, Room 4138D
Charlestown, MA 02129
Tel: 617-792-8197
Fax: 617-726-5806
Email: gburns@cvrc.mgh.harvard.edu
Visit my lab page here.



Research in the Burns Laboratory is devoted to understanding how cardiovascular progenitor cells build the vertebrate heart during embryonic development and how, in certain vertebrate species such as the zebrafish, the heart can fully regenerate following injury. In the embryo, we are particularly interested in a recently identified late-differentiating pool of cardiovascular progenitors, called the anterior second heart field (SHF), that is responsible for building the right ventricle and outflow tract in higher vertebrates. Defects in human SHF development cause common complex congenital cardiac malformations including Tetralogy of Fallot and Double Outlet Right Ventricle. Even though the zebrafish heart does not have the anatomic equivalent of a right ventricle, we discovered that the SHF is conserved in zebrafish. Using lineage tracing, we determined that the zebrafish SHF gives rise to a significant portion of cardiomyocytes in the ventricle and three cardiovascular lineages in the outflow tract. Using genetic and small molecule loss-of-function analysis, we implicated TGFβ-signaling in promoting proliferation of SHF progenitors to balance SHF differentiation. More recently, we have demonstrated that the timing and location of SHF specification are conserved in zebrafish and that the essential functions of two cardiac transcription factors during SHF development are also conserved in zebrafish. Current laboratory efforts are devoted to using unbiased approaches (genetic and small molecule screens) to identify novel regulators of SHF development. We are also generating the necessary tools to perform in vivo clonal analysis to determine when SHF progenitors are segregated from other cardiovascular progenitors.

The second embryonic process of interest to our laboratory is pharyngeal arch artery (PAA) development. PAAs are paired bilateral embryonic vessels that undergo remodeling and give rise to essential segments of the aorta, pulmonary artery, and carotid arteries in higher vertebrates. In humans, defects in PAA development or remodeling are common causes of congenital malformations of the aorta. The zebrafish PAAs are not remodeled but the initial configuration of the PAAs is conserved. In recent work, we have identified the classically defined heart field as the embryonic source of PAA endothelium. Using loss of function analysis, we have implicated the cardiac transcription factor Nkx2.5 in controlling the endothelial differentiation of angioblasts. Current efforts are devoted to discovering novel small molecules that disrupt PAA formation as an unbiased approach to identify novel regulators of this process.

Another major focus of the laboratory is cardiac regeneration. In humans, cardiac injury induces scar formation rather than regeneration. The holy grail of cardiovascular medicine is to understand the barriers to cardiomyocyte regeneration in humans and devise new therapeutic approaches to overcome them. The zebrafish heart regenerates myocardium robustly following several different forms of injury. Myocardial regeneration relies on proliferation of uninjured cardiomyocytes but the extrinsic and intrinsic factors that stimulate cardiomyocyte proliferation are not well defined. We have recently implicated Notch signaling in the control of zebrafish cardiomyocyte proliferation and cardiac regeneration. Notch receptors are induced in the endocardium and epicardium, but not the myocardium, following injury. Inhibition of Notch signaling using a dominant negative approach impairs cardiac regeneration by inhibiting cardiomyocyte proliferation. Because Notch signaling is high in the endocardium and epicardium but the proliferation defect is seen in the myocardium, we hypothesize that a Notch dependent myocardial proliferation signal is released from the endocardium and epicardium following injury. Current efforts are underway to identify this Notch dependent proliferation signal. We are also devising novel transgenic tools to probe the genetic pathways controlling cardiomyocyte proliferation in the embryo on the assumption that many of the same pathways are controlling cardiomyocyte proliferation in the embryo and regenerating heart.



Last Update: 8/21/2013



Publications

For a complete listing of publications click here.

 


 

Deacon DC, Nevis KR, Cashman TJ, Zhou Y, Zhao L, Washko D, Guner-Ataman B, Burns CG*, Burns CE*. The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis. Development. 2010 137:1887-96. (* equal contribution)

Zhou Y, Cashman TJ, Nevis KR, Obregon P, Carney SA, Liu Y, Gu A, Mosimann C, Sondalle S, Peterson RE, Heideman W, Burns CE*,
Burns CG*. Latent TGFb binding protein 3 identifies a second heart field in zebrafish. Nature. 2011 474:645-8. (* equal contribution)

Guner-Ataman B, Paffett-Lugassy N, Adams MA, Nevis KR, Jahangiri L, Obregon P, Kikuchi K, Poss KD, Burns CE*,
Burns CG*. Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function. Development. 2013 40:1353-1363. (* equal contribution)

Nevis KR, Obregon P, Walsh C, Guner-Ataman B,
Burns, CG*, Burns CE*. (In Press). Tbx1 is required for second heart field proliferation in zebrafish. Developmental Dynamics. 2013 242:540-9. (* equal contribution)



© 2013 by the President and Fellows of Harvard College