PUBLICATION

CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

Authors

Matrone, G., Wilson, K.S., Maqsood, S., Mullins, J.J., Tucker, C.S., Denvir, M.A.

ID

ZDB-PUB-151107-2

Date

2015

Source

Journal of Cell Science 128(24): 4560-71 (Journal)

Registered Authors

Mullins, John

Keywords

Zebrafish, CDK9, LARP7, Heart, Repair

MeSH Terms

Animals
Cell Proliferation*
Cyclin-Dependent Kinase 9/genetics
Cyclin-Dependent Kinase 9/metabolism*
Heart Injuries/genetics
Heart Injuries/metabolism*
Heart Injuries/pathology
Myocytes, Cardiac/metabolism*
Myocytes, Cardiac/pathology
RNA Polymerase II/genetics
RNA Polymerase II/metabolism
Ribonucleoproteins/genetics
Ribonucleoproteins/metabolism*
Zebrafish/genetics
Zebrafish/metabolism*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*

(all 17)

PubMed

26542022 Full text @ J. Cell Sci.

Abstract

Cyclin Dependent Kinase (CDK)9 acts via the Positive Transcription Elongation Factor-b (P-TEFb) complex to activate and expand transcription via RNA polymerase II (RNApol II). It has also been shown to regulate cardiomyocyte hypertrophy with recent evidence linking it to cardiomyocyte proliferation. We hypothesised that modification of CDK9 activity could both impair and enhance the cardiac response to injury by modifying cardiomyocyte proliferation.CDK9 expression and activity were inhibited in the zebrafish (Danio rerio) embryo. We show that dephosphorylation of the Serine2 residue on the Carboxy-Terminal domain of RNApol II (Ser2-RNApol II-CTD) is associated with impaired cardiac structure, function and cardiomyocyte proliferation and also results in impaired functional recovery following cardiac laser injury. In contrast, de-repression of CDK9 activity, by knockdown of La-related protein (LARP7) increases phosphorylation of Ser2-RNApol II-CTD and increases cardiomyocyte proliferation. LARP7 knockdown rescued the structural and functional phenotype associated with knockdown of CDK9.CDK9/LARP7-balance plays a key role in cardiomyocyte proliferation and response to injury. LARP7 represents a potentially novel therapeutic target in promoting cardiomyocyte proliferation and recovery from injury.

Genes / Markers

Marker	Marker Type	Name
cdk9	GENE	cyclin-dependent kinase 9 (CDC2-related kinase)
gata4	GENE	GATA binding protein 4
gata5	GENE	GATA binding protein 5
gata6	GENE	GATA binding protein 6
larp7	GENE	La ribonucleoprotein 7, transcriptional regulator

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Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
f1Tg	chemical treatment: alvocidib	Long-pec	whole organism gata4 expression decreased amount, abnormal	Fig. 6
f1Tg	chemical treatment: alvocidib	Long-pec	whole organism Ab3-polr2a labeling decreased amount, abnormal	Fig. 2
f1Tg	chemical treatment: alvocidib	Protruding-mouth	cardiac muscle cell decreased amount, abnormal	Fig. 7
f1Tg	chemical treatment: alvocidib	Protruding-mouth	cardiac muscle contraction process quality, abnormal	Fig. 3
f1Tg	chemical treatment: alvocidib	Protruding-mouth	cardiac ventricle cardiac muscle cell decreased amount, abnormal	Fig. 5
f1Tg	chemical treatment: alvocidib	Protruding-mouth	cardiac ventricle cardiac muscle cell proliferation decreased occurrence, abnormal	Fig. 5
f1Tg	chemical treatment: alvocidib	Protruding-mouth	heart decreased size, abnormal	Fig. 3
f1Tg	chemical treatment: alvocidib	Protruding-mouth	whole organism ab3-cdk9 labeling increased amount, abnormal	Fig. 2
f1Tg	chemical treatment: alvocidib	Protruding-mouth	whole organism Ab3-polr2a labeling decreased amount, abnormal	Fig. 2
f1Tg	chemical treatment: alvocidib	Day 4	cardiac muscle contraction process quality, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
f1Tg	Tg(myl7:GFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cdk9	MO3-cdk9	MRPHLNO
cdk9	MO13-cdk9	MRPHLNO
larp7	MO2-larp7	MRPHLNO
larp7	MO3-larp7	MRPHLNO

Fish

Fish
f1Tg
f1Tg + MO2-larp7
f1Tg + MO2-larp7 + MO3-cdk9
f1Tg + MO3-cdk9
f1Tg + MO3-larp7
f1Tg + MO13-cdk9

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Matrone et al., 2015 ZDB-PUB-151107-2 PMID:26542022

CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

Matrone et al., 2015

ZDB-PUB-151107-2
PMID:26542022