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

Animals
Zebrafish/embryology*
Zebrafish/genetics
Trans-Activators/genetics
Trans-Activators/metabolism*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Myocytes, Cardiac/metabolism*
Protein Stability
Heart/embryology*
Cell Cycle Proteins/genetics
Cell Cycle Proteins/metabolism*

(all 12)

PubMed

32843528 Full text @ Development

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

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ccn1	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
ccn2a	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
clu	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
GFP	mw43Tg + MO1-llgl1	standard conditions	Long-pec	heart	IFL	Fig. 5
hbegfa	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
lats2	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
llgl1	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
llgl2	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6
pawr	WT + MO1-llgl1	standard conditions	Protruding-mouth	heart	RTPCR	Fig. 6

1 - 9 of 9

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-llgl1	standard conditions	Long-pec	cardiac muscle cell hypertrophic, abnormal	Fig. 3
WT + MO1-llgl1	standard conditions	Long-pec	cardiac muscle cell intercalated disc morphology, abnormal	Fig. S7
WT + MO1-llgl1	standard conditions	Long-pec	cardiac muscle cell sarcomere decreased amount, abnormal	Fig. S7
WT + MO1-llgl1	standard conditions	Long-pec	cardiac ventricle cardiac muscle cell Ab4-yap1 labeling decreased amount, abnormal	Fig. 6
WT + MO1-llgl1	standard conditions	Long-pec	cardiac ventricle cardiac muscle cell circular, abnormal	Fig. 3
WT + MO1-llgl1	standard conditions	Long-pec	cardiac ventricle cardiac muscle cell circular, abnormal	Fig. S6
WT + MO1-llgl1	standard conditions	Long-pec	cardiac ventricle morphology, abnormal	Fig. S5
WT + MO1-llgl1	standard conditions	Long-pec	heart looping disrupted, abnormal	Fig. S5
WT + MO1-llgl1	standard conditions	Long-pec	heart valve morphogenesis process quality, abnormal	Fig. 5
WT + MO1-llgl1	standard conditions	Long-pec	heart valve morphogenesis process quality, abnormal	Fig. S8

1 - 10 of 49

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
mw43Tg	Tg(EPV.TP1-Mmu.Hbb:d2GFP)	Transgenic Insertion
mw45Tg	Tg(UAS:mKOFP2,myl7:EGFP)	Transgenic Insertion
mw83		Small Deletion	llgl1

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
llgl1	MO1-llgl1	MRPHLNO
llgl1	TALEN1-llgl1	TALEN

Fish

Fish
llgl1^mw83/mw83
llgl1^mw83/mw83
llgl1^mw83/mw83; mw45Tg
mw43Tg + MO1-llgl1
WT + MO1-llgl1

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP
mKOFP2	EFG	mKOFP2

Mapping

Flinn et al., 2020 ZDB-PUB-200828-4 PMID:32843528

Llgl1 regulates zebrafish cardiac development by mediating Yap stability in cardiomyocytes

Flinn et al., 2020

ZDB-PUB-200828-4
PMID:32843528