Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species
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
DOI:
10.1083/jcb.201006114
Publication Date:
2011-06-21T03:52:07Z
AUTHORS (24)
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.
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CITATIONS (74)
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