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: 9.67). 09/2007; 104(35):14008-13. DOI: 10.1073/pnas.0702240104
Source: PubMed


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.

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    • "To determine endogenous hey2/grl expression, we performed WISH study of grl expression during embryonic zebrafish development (Figure S1). Grl expression is observed only at the LPM as shown previously [10], and at the midline (Figure S1). Notch1 and Notch4 are the endothelial specific Notch [11]. "
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    • "transcriptional activity leading to inhibition of myocardial proliferation (Jia et al., 2007). By contrast, the hearts of the zebrafish mutants heart of glass (heg), santa (san) and valentine (val) do not show concentric growth because they fail to add additional myocardial cell layers, even though the total cell number is not altered. "
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