title: CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart.
abstract: Cyclin dependent kinase (Cdk)9 acts through the positive transcription elongation factor-b (P-TEFb) complex to activate and expand transcription through RNA polymerase 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 residue Ser2 on the C-terminal domain of RNA polymerase II is associated with impaired cardiac structure and function, and cardiomyocyte proliferation and also results in impaired functional recovery following cardiac laser injury. In contrast, de-repression of Cdk9 activity, through knockdown of La-related protein (Larp7) increases phosphorylation of Ser2 in RNA polymerase II and increases cardiomyocyte proliferation. Larp7 knockdown rescued the structural and functional phenotype associated with knockdown of Cdk9. The balance of Cdk9 and Larp7 plays a key role in cardiomyocyte proliferation and response to injury. Larp7 represents a potentially novel therapeutic target to promote cardiomyocyte proliferation and recovery from injury.
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Matrone
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Wilson
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Sana
authors.initials: S
authors.lastname: Maqsood
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Tucker
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK mdenvir@staffmail.ed.ac.uk.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Denvir
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D006335:Heart Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012261:Ribonucleoproteins; D029961:Zebrafish Proteins; C517155:Cdk9 protein, zebrafish; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II
keywords: CDK9; Heart; LARP7; Repair; Zebrafish