PUBLICATION

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Authors

Jia, H., King, I.N., Chopra, S.S., Wan, H., Ni, T.T., Jiang, C., Guan, X., Wells, S., Srivastava, D., and Zhong, T.P.

ID

ZDB-PUB-070827-23

Date

2007

Source

Proceedings of the National Academy of Sciences of the United States of America 104(35): 14008-14013 (Journal)

Registered Authors

Wan, Haiyan, Zhong, Tao P.

Keywords

cardiomyocyte, proliferation, size control, transcription

MeSH Terms

Animals
Basic Helix-Loop-Helix Transcription Factors/genetics*
Cell Division
Embryonic Development
GATA5 Transcription Factor/genetics*
Gene Expression Regulation, Developmental
Genes, Reporter
Heart/anatomy & histology
Heart/embryology
Heart/growth & development*
Molecular Sequence Data
Myocytes, Cardiac/cytology
Myocytes, Cardiac/physiology*
Zebrafish
Zebrafish Proteins/genetics*

(all 15)

PubMed

17715064 Full text @ Proc. Natl. Acad. Sci. USA

Abstract

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.

Genes / Markers

Marker	Marker Type	Name
egr1	GENE	early growth response 1
fosab	GENE	v-fos FBJ murine osteosarcoma viral oncogene homolog Ab
gata4	GENE	GATA binding protein 4
gata5	GENE	GATA binding protein 5
hey2	GENE	hes-related family bHLH transcription factor with YRPW motif 2
junba	GENE	JunB proto-oncogene, AP-1 transcription factor subunit a
myh6	GENE	myosin, heavy chain 6, cardiac muscle, alpha
myh7	GENE	myosin heavy chain 7
myl7	GENE	myosin, light chain 7, regulatory
nkx2.5	GENE	NK2 homeobox 5

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
egr1	hey2^m145/m145	standard conditions	Long-pec	whole organism	RTPCR	Fig. 1
egr1	hey2^vu59/vu59	standard conditions	Protruding-mouth	heart	ISH	Fig. 1
egr1	WT	standard conditions	Protruding-mouth	heart	ISH	Fig. 1
fosab	hey2^m145/m145	standard conditions	Long-pec	whole organism	RTPCR	Fig. 1
gata4	hey2^m145/m145	standard conditions	5-9 somites	heart primordium	ISH	Fig. 1
gata4	WT	standard conditions	5-9 somites	heart primordium	ISH	Fig. 1
hey2	WT	standard conditions	1-4 somites	anterior lateral plate mesoderm	ISH	Fig. 7
hey2	WT	standard conditions	5-9 somites	anterior lateral plate mesoderm	ISH	Fig. 7
hey2	WT	standard conditions	Long-pec	atrioventricular ring	ISH	Fig. 7
hey2	WT	standard conditions	Long-pec	atrium	ISH	Fig. 7

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-gata5	standard conditions	Long-pec	heart cardiac muscle cell decreased amount, abnormal	Fig. 5
WT + MO1-gata5	standard conditions	Long-pec	heart decreased size, abnormal	Fig. 5
hey2^m145/m145	control	Long-pec	heart increased size, abnormal	Fig. 5
hey2^m145/m145	standard conditions	Long-pec	heart sarcomere increased size, abnormal	Fig. 1
hey2^m145/m145	standard conditions	Protruding-mouth	atrial myocardium cardiac muscle cell decreased mass density, abnormal	Fig. 2
hey2^m145/m145	standard conditions	Protruding-mouth	atrial myocardium cardiac muscle cell increased amount, abnormal	Fig. 2
hey2^m145/m145	standard conditions	Protruding-mouth	atrium increased size, abnormal	Fig. 2
hey2^m145/m145	standard conditions	Protruding-mouth	cardiac muscle cell sarcomere structure, normal	Fig. 2
hey2^m145/m145	standard conditions	Protruding-mouth	cardiac ventricle decreased size, abnormal	Fig. 2
hey2^m145/m145	standard conditions	Protruding-mouth	heart cardiac muscle cell increased size, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
f1Tg	Tg(myl7:GFP)	Transgenic Insertion
m145		Point Mutation	hey2
vu59		Point Mutation	hey2
zf80		Point Mutation	hey2

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
gata5	MO1-gata5	MRPHLNO

Fish

Fish
f1Tg/+
hey2^m145/m145
hey2^m145/m145; f1Tg/+
hey2^m145/m145 + MO1-gata5
hey2^vu59/vu59
hey2^zf80/zf80
WT
WT + MO1-gata5

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Jia et al., 2007 ZDB-PUB-070827-23 PMID:17715064

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Jia et al., 2007

ZDB-PUB-070827-23
PMID:17715064