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Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species.

Unraveling the gene regulatory networks that govern development and function of the mammalian heart is critical for the rational design of therapeutic interventions in human heart disease. Using the Drosophila heart as a platform for identifying novel gene interactions leading to heart disease, we found that the Rho-GTPase Cdc42 cooperates with the cardiac transcription factor Tinman/Nkx2-5. Compound Cdc42, tinman heterozygous mutant flies exhibited impaired cardiac output and altered myofibrillar architecture, and adult heart-specific interference with Cdc42 function is sufficient to cause these same defects. We also identified K(+) channels, encoded by dSUR and slowpoke, as potential effectors of the Cdc42-Tinman interaction. To determine whether a Cdc42-Nkx2-5 interaction is conserved in the mammalian heart, we examined compound heterozygous mutant mice and found conduction system and cardiac output defects. In exploring the mechanism of Nkx2-5 interaction with Cdc42, we demonstrated that mouse Cdc42 was a target of, and negatively regulated by miR-1, which itself was negatively regulated by Nkx2-5 in the mouse heart and by Tinman in the fly heart. We conclude that Cdc42 plays a conserved role in regulating heart function and is an indirect target of Tinman/Nkx2-5 via miR-1.

Pubmed ID: 21690310


  • Qian L
  • Wythe JD
  • Liu J
  • Cartry J
  • Vogler G
  • Mohapatra B
  • Otway RT
  • Huang Y
  • King IN
  • Maillet M
  • Zheng Y
  • Crawley T
  • Taghli-Lamallem O
  • Semsarian C
  • Dunwoodie S
  • Winlaw D
  • Harvey RP
  • Fatkin D
  • Towbin JA
  • Molkentin JD
  • Srivastava D
  • Ocorr K
  • Bruneau BG
  • Bodmer R


The Journal of cell biology

Publication Data

June 27, 2011

Associated Grants

  • Agency: NHLBI NIH HHS, Id: K99 HL109079
  • Agency: NHLBI NIH HHS, Id: R01 HL054732
  • Agency: NHLBI NIH HHS, Id: R01 HL085481
  • Agency: NHLBI NIH HHS, Id: T32HL007731

Mesh Terms

  • Animals
  • Drosophila
  • Drosophila Proteins
  • GTP-Binding Proteins
  • Gene Expression Regulation, Developmental
  • Heart
  • Heart Diseases
  • Homeodomain Proteins
  • Humans
  • Mice
  • MicroRNAs
  • Myocardial Contraction
  • Myocardium
  • Myocytes, Cardiac
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins