PUBLICATION
Llgl1 regulates zebrafish cardiac development by mediating Yap stability in cardiomyocytes
- Authors
- Flinn, M.A., Otten, C., Brandt, Z.J., Bostrom, J.R., Kenarsary, A., Wan, T.C., Auchampach, J.A., Abdelilah-Seyfried, S., O'Meara, C.C., Link, B.A.
- ID
- ZDB-PUB-200828-4
- Date
- 2020
- Source
- Development (Cambridge, England) 147(16): (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim, Link, Brian
- Keywords
- Cardiac development, Hippo-Yap pathway, Valvulogenesis, Zebrafish
- MeSH Terms
-
- Heart/embryology*
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism*
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Myocytes, Cardiac/metabolism*
- Animals
- Trans-Activators/genetics
- Trans-Activators/metabolism*
- Protein Stability
- PubMed
- 32843528 Full text @ Development
Citation
Flinn, M.A., Otten, C., Brandt, Z.J., Bostrom, J.R., Kenarsary, A., Wan, T.C., Auchampach, J.A., Abdelilah-Seyfried, S., O'Meara, C.C., Link, B.A. (2020) Llgl1 regulates zebrafish cardiac development by mediating Yap stability in cardiomyocytes. Development (Cambridge, England). 147(16):.
Abstract
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 Hippo-mediated 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, cardiomyocyte-specific 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping