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Burns, Caroline

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Burns

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Caroline

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Burns, Caroline
Author's Publications: search.filters.isAuthorOfPublication.4cdc127b-d904-4f57-946d-4ff0036a45b1

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Now showing 1 - 7 of 7
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    Zebrafish heart regeneration: 15 years of discoveries
    (John Wiley and Sons Inc., 2017) González‐Rosa, Juan Manuel; Burns, Caroline; Burns, C. Geoffrey
    Abstract Cardiovascular disease is the leading cause of death worldwide. Compared to other organs such as the liver, the adult human heart lacks the capacity to regenerate on a macroscopic scale after injury. As a result, myocardial infarctions are responsible for approximately half of all cardiovascular related deaths. In contrast, the zebrafish heart regenerates efficiently upon injury through robust myocardial proliferation. Therefore, deciphering the mechanisms that underlie the zebrafish heart's endogenous regenerative capacity represents an exciting avenue to identify novel therapeutic strategies for inducing regeneration of the human heart. This review provides a historical overview of adult zebrafish heart regeneration. We summarize 15 years of research, with a special focus on recent developments from this fascinating field. We discuss experimental findings that address fundamental questions of regeneration research. What is the origin of regenerated muscle? How is regeneration controlled from a genetic and molecular perspective? How do different cell types interact to achieve organ regeneration? Understanding natural models of heart regeneration will bring us closer to answering the ultimate question: how can we stimulate myocardial regeneration in humans?
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    Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis
    (2013) Paffett-Lugassy, Noëlle; Singh, Reena; Nevis, Kathleen R.; Guner-Ataman, Burcu; O'Loughlin, Evan; Jahangiri, Leila; Harvey, Richard P.; Burns, C. Geoffrey; Burns, Caroline
    The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that make indispensable contributions to the carotid arteries and great vessels of the heart, including the aorta and pulmonary artery1, 2. During embryogenesis, the PAAs appear in a craniocaudal sequence to connect pre-existing segments of the primitive circulation after de novo vasculogenic assembly from angioblast precursors3, 4. Despite the unique spatiotemporal characteristics of PAA development, the embryonic origins of PAA angioblasts and the genetic factors regulating their emergence remain unknown. Here, we identify the embryonic source of PAA endothelium as nkx2.5+ progenitors in lateral plate mesoderm long considered to adopt cell fates within the heart exclusively5, 6. Further, we report that PAA endothelial differentiation relies on Nkx2.5, a canonical cardiac transcription factor not previously implicated in blood vessel formation. Together, these studies reveal the heart field origin of PAA endothelium and attribute a novel vasculogenic function to the cardiac transcription factor nkx2.5 during great vessel precursor development.
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    Hematopoietic Defects in rps29 Mutant Zebrafish Depend Upon p53 Activation
    (Elsevier BV, 2012) Taylor, Alison; Humphries, Jessica M.; White, Richard; Murphey, Ryan D.; Burns, Caroline; Zon, Leonard
    Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Black- fan anemia, a rare congenital disease characterized by red cell aplasia and distinctive cranio- facial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29L/L embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes upregulated in the rps29 mutant are enriched for genes upregulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 medi- ates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in hematopoietic stem cells and red blood cell development.
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    Characterization of immune-matched hematopoietic transplantation in zebrafish
    (American Society of Hematology, 2011) de Jong, J. L. O.; Burns, Caroline; Chen, A. T.; Pugach, E.; Mayhall, E. A.; Smith, A. C. H.; Feldman, Henry; Zhou, Yi; Zon, Leonard
    Evaluating hematopoietic stem cell (HSC) function in vivo requires a long-term transplantation assay. Although zebrafish are a powerful model for discovering the genetics of hematopoiesis, hematopoietic transplantation approaches have been underdeveloped. Here we established a long-term reconstitution assay in adult zebrafish. Primary and secondary recipients showed multilineage engraftment at 3 months after transplantation. Limiting dilution data suggest that at least 1 in 65 000 zebrafish marrow cells contain repopulating activity, consistent with mammalian HSC frequencies. We defined zebrafish haplotypes at the proposed major histocompatibility complex locus on chromosome 19 and tested functional significance through hematopoietic transplantation. Matching donors and recipients dramatically increased engraftment and percentage donor chimerism compared with unmatched fish. These data constitute the first functional test of zebrafish histocompatibility genes, enabling the development of matched hematopoietic transplantations. This lays the foundation for competitive transplantation experiments with mutant zebrafish HSCs and chemicals to test for effects on engraftment, thereby providing a model for human hematopoietic diseases and treatments not previously available.
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    Chamber identity programs drive early functional partitioning of the heart
    (Nature Pub. Group, 2015) Mosimann, Christian; Panáková, Daniela; Werdich, Andreas; Musso, Gabriel; Burger, Alexa; Lawson, Katy L.; Carr, Logan A.; Nevis, Kathleen R.; Sabeh, M. Khaled; Zhou, Yi; Davidson, Alan J.; DiBiase, Anthony; Burns, Caroline; Burns, C. Geoffrey; MacRae, Calum; Zon, Leonard
    The vertebrate heart muscle (myocardium) develops from the first heart field (FHF) and expands by adding second heart field (SHF) cells. While both lineages exist already in teleosts, the primordial contributions of FHF and SHF to heart structure and function remain incompletely understood. Here we delineate the functional contribution of the FHF and SHF to the zebrafish heart using the cis-regulatory elements of the draculin (drl) gene. The drl reporters initially delineate the lateral plate mesoderm, including heart progenitors. Subsequent myocardial drl reporter expression restricts to FHF descendants. We harnessed this unique feature to uncover that loss of tbx5a and pitx2 affect relative FHF versus SHF contributions to the heart. High-resolution physiology reveals distinctive electrical properties of each heart field territory that define a functional boundary within the single zebrafish ventricle. Our data establish that the transcriptional program driving cardiac septation regulates physiologic ventricle partitioning, which successively provides mechanical advantages of sequential contraction.
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    Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration
    (Proceedings of the National Academy of Sciences, 2014) Zhao, Long; Borikova, Asya; Ben-Yair, Raz; Guner-Ataman, Burcu; MacRae, Calum; Lee, Richard; Burns, Charles; Burns, Caroline
    The human heart’s failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling.
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    Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis
    (2016) Han, Peidong; Bloomekatz, Joshua; Ren, Jie; Zhang, Ruilin; Grinstein, Jonathan D.; Zhao, Long; Burns, C. Geoffrey; Burns, Caroline; Anderson, Ryan M.; Chi, Neil C.
    Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart is comprised of an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease (CHD)1 and non-compaction cardiomyopathies2, it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here, we utilize advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signaling that directs the spatial allocation of myocardial cells to their proper morphologic positions in the ventricular wall. Although previous studies have shown that endocardial Notch signaling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and BMP signaling3, we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signaling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness due to excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell thick wall but no trabeculae. Notably, this myocardial Notch signaling is activated non-cell-autonomously by neighboring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provides insight into the cellular dynamics of how diverse cell lineages organize to create form.