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Citation
Qian, L., Wythe, J.D., Liu, J., Cartry, J., Vogler, G., Mohapatra, B., Otway, R.T., Huang, Y., King, I.N., Maillet, M., Zheng, Y., Crawley, T., Taghli-Lamallem, O., Semsarian, C., Dunwoodie, S., Winlaw, D., Harvey, R.P., Fatkin, D., Towbin, J.A., Molkentin, J.D., Srivastava, D., Ocorr, K., Bruneau, B.G., Bodmer, R. (2011). Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species.  J. Cell Biol. 193(7): 1181--1196.
FlyBase ID
FBrf0213988
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC3216339 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    J. Cell Biol.
    Title
    Journal of Cell Biology
    Publication Year
    1966-
    ISBN/ISSN
    0021-9525
    Data From Reference
    Aberrations (97)
    Alleles (9)
    Genes (7)
    Insertions (1)
    Transgenic Constructs (4)