Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Drosophila / genetics
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Drosophila / metabolism
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Drosophila / physiology*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila Proteins / physiology*
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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GTP-Binding Proteins / physiology
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Gene Expression Regulation, Developmental
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Heart / physiology*
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Heart Diseases / genetics
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Humans
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Mice
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MicroRNAs / physiology*
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Myocardial Contraction / genetics
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Myocardium / metabolism
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Myocytes, Cardiac / cytology
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors / genetics
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Transcription Factors / physiology*
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism*
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cdc42 GTP-Binding Protein / physiology
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rho GTP-Binding Proteins / metabolism
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rho GTP-Binding Proteins / physiology
Substances
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Cdc42 protein, Drosophila
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Drosophila Proteins
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins
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MIRN1 microRNA, Drosophila
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MicroRNAs
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Mirn1 microRNA, mouse
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Nkx2-5 protein, mouse
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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tin protein, Drosophila
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GTP-Binding Proteins
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cdc42 GTP-Binding Protein
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rho GTP-Binding Proteins