Faculty Collaboration Database

Llgl1 regulates zebrafish cardiac development by mediating Yap stability in cardiomyocytes. Development 2020 Aug 25;147(16)

Date

08/28/2020

Pubmed ID

32843528

Pubmed Central ID

PMC7473637

DOI

10.1242/dev.193581

Scopus ID

2-s2.0-85089923843 (requires institutional sign-in at Scopus site)   7 Citations

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.

Author List

Flinn MA, Otten C, Brandt ZJ, Bostrom JR, Kenarsary A, Wan TC, Auchampach JA, Abdelilah-Seyfried S, O'Meara CC, Link BA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Michael Andrew Flinn Postdoctoral Fellow in the Physiology department at Medical College of Wisconsin
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Cycle Proteins
Heart
Myocytes, Cardiac
Protein Stability
Trans-Activators
Zebrafish
Zebrafish Proteins