Journal
DEVELOPMENT
Volume 147, Issue 16, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.193581
Keywords
Hippo-Yap pathway; Valvulogenesis; Cardiac development; Zebrafish
Categories
Funding
- Cardiovascular Center and Research and Education Program Fund at the Medical College of Wisconsin
- Advancing a Healthier Wisconsin Co-Investigator Grant
- National Institutes of Health [R01 HL141159, 5R01HL131788, 1S10 OD025038, T32 HL134643]
- Cardiovascular Center's A.O. Smith Fellowship Scholars Program
- Medical College of Wisconsin Cardiovascular Center [FP00012308]
- Excellence cluster REBIRTH [SFB958]
- Deutsche Forschungsgemeinschaft [SE2016/7-2, SE2016/10-1]
- Deutsches Zentrum fur Herz-Kreislaufforschung
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The Hippo-Yap pathway regulates multiple cellular processes in response to mechanical and other stimuli. In Drosophila, the polarity protein Lethal (2) giant larvae [L(2)gl], negatively regulates Hippomediated transcriptional output. However, in vertebrates, little is known about its homolog Llgl1. Here, we define a novel role for vertebrate Llgl1 in regulating Yap stability in cardiomyocytes, which impacts heart development. In contrast to the role of Drosophila L(2)gl, Llgl1 depletion in cultured rat cardiomyocytes decreased Yap protein levels and blunted target gene transcription without affecting Yap transcript abundance. Llgl1 depletion in zebrafish resulted in larger and dysmorphic cardiomyocytes, pericardial effusion, impaired blood flow and aberrant valvulogenesis. Cardiomyocyte Yap protein levels were decreased in llgl1 morphants, whereas Notch, which is regulated by hemodynamic forces and participates in valvulogenesis, was more broadly activated. Consistent with the role of Llgl1 in regulating Yap stability, cardiomyocytespecific overexpression of Yap in Llgl1-depleted embryos ameliorated pericardial effusion and restored blood flow velocity. Altogether, our data reveal that vertebrate Llgl1 is crucial for Yap stability in cardiomyocytes and its absence impairs cardiac development.
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