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

• DOI: 10.1083/jcb.201006114
• Publication Date: 2011-06-21T03:52:07Z
• Authors: Li Qian; Joshua D. Wythe; Jiandong Liu; Jerome Cartry; Georg Vogler; Bhagyalaxmi Mohap...; Robyn T. Otway; Yu Huang; Isabelle N. King; Marjorie Maillet; Yi Zheng; Timothy Crawley; Ouarda Taghli-Lam...; Christopher Semsa...; Sally Dunwoodie; David Winlaw; Richard P. Harvey; Diane Fatkin; Jeffrey A. Towbin; Jeffery D. Molkentin; Deepak Srivastava; Karen Ocorr; Benoit G. Bruneau; Rolf Bodmer
• Keywords: rho GTP-Binding Proteins; Biomedical and clinical sciences; Cardiovascular; Medical and Health Sciences; anzsrc-for: 110201 Cardiology (incl. Cardiovascular Diseases); Mice; 2.1 Biological and endogenous factors; Drosophila Proteins; Developmental; Myocytes, Cardiac; anzsrc-for: 31 Biological Sciences; cdc42 GTP-Binding Protein; Research Articles; 0303 health sciences; anzsrc-for: 3101 Biochemistry and Cell Biology; Gene Expression Regulation, Developmental; Heart; Biological Sciences; 3. Good health; Biological sciences; Heart Disease; Homeobox Protein Nkx-2.5; Drosophila; Cardiac; Biotechnology; 570; Heart Diseases; 1.1 Normal biological development and functioning; 610; 3101 Biochemistry and Cell Biology; 03 medical and health sciences; GTP-Binding Proteins; Genetics; Animals; Humans; Homeodomain Proteins; Myocytes; Myocardium; Myocardial Contraction; Repressor Proteins; anzsrc-for: 32 Biomedical and clinical sciences; MicroRNAs; anzsrc-for: 11 Medical and Health Sciences; Gene Expression Regulation; anzsrc-for: 06 Biological Sciences; Trans-Activators; Biochemistry and Cell Biology; 31 Biological Sciences; Developmental Biology; Transcription Factors

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.