Article

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5.

Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2007; 104(35):14008-13. DOI: 10.1073/pnas.0702240104
Source: PubMed

ABSTRACT Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5-mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression.

0 Bookmarks
 · 
116 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have developed a robust in vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells. In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.
    Chemistry & biology 12/2011; 18(12):1658-68. · 6.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral cavernous malformation is a clinically well-defined microvascular disorder predisposing to stroke; however, the major phenotype observed in zebrafish is the cardiac defect, specifically an enlarged heart. Less effort has been made to explore this phenotypic discrepancy between human and zebrafish. Given the fact that the gene products from Ccm1/Ccm2 are nearly identical between the two species, the common sense has dictated that the zebrafish animal model would provide a great opportunity to dissect the detailed molecular function of Ccm1/Ccm2 during angiogenesis. We recently reported on the cellular role of the Ccm1 gene in biochemical processes that permit proper angiogenic microvascular development in the zebrafish model. In the course of this experimentation, we encountered a vast amount of recent research on the relationship between dysfunctional angiogenesis and cardiovascular defects in zebrafish. Here we compile the findings of our research with the most recent contributions in this field and glean conclusions about the effect of defective angiogenesis on the developing cardiovascular system. Our conclusion also serves as a bridge for the phenotypic discrepancy between humans and animal models, which might provide some insights into future translational research on human stroke.
    Translational Stroke Research 09/2011; 2(3):339-345.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The zebrafish has become an ideal vertebrate animal system for investigating cardiac development due to its genetic tractability, external fertilization, early optical clarity and ability to survive without a functional cardiovascular system during development. In particular, recent advances in imaging techniques and the creation of zebrafish transgenics now permit the in vivo analysis of the dynamic cellular events that transpire during cardiac morphogenesis. As a result, the combination of these salient features provides detailed insight as to how specific genes may influence cardiac development at the cellular level. In this review, we will highlight how the zebrafish has been utilized to elucidate not only the underlying mechanisms of cardiac development and human congenital heart diseases (CHDs), but also potential pathways that may modulate cardiac regeneration. Thus, we have organized this review based on the major categories of CHDs-structural heart, functional heart, and vascular/great vessel defects, and will conclude with how the zebrafish may be further used to contribute to our understanding of specific human CHDs in the future.
    Differentiation 06/2012; 84(1):4-16. · 2.86 Impact Factor

Full-text

View
0 Downloads
Available from