ZFIN ID: ZDB-PUB-151107-2
CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart
Matrone, G., Wilson, K.S., Maqsood, S., Mullins, J.J., Tucker, C.S., Denvir, M.A.
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*
PubMed: 26542022 Full text @ J. Cell Sci.
FIGURES
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.
ADDITIONAL INFORMATION