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

Li Qian, Joshua D. Wythe, Jiandong Liu, Jerome Cartry, Georg Vogler, Bhagyalaxmi Mohapatra, Robyn T. Otway, Yu Huang, Isabelle N. King, Marjorie Maillet, Yi Zheng, Timothy Crawley, Ouarda Taghli-Lamallem, Christopher Semsarian, Sally Dunwoodie, David Winlaw, Richard P. Harvey, Diane Fatkin, Jeffrey Towbin, Jeffery D. Molkentin & 4 others Deepak Srivastava, Karen Ocorr, Benoit G. Bruneau, Rolf Bodmer

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1181-1196
Number of pages16
JournalJournal of Cell Biology
Volume193
Issue number7
DOIs
StatePublished - Jun 27 2011

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Diptera
Cardiac Output
Heart Diseases
rho GTP-Binding Proteins
Gene Regulatory Networks
Drosophila
Transcription Factors
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Qian, L., Wythe, J. D., Liu, J., Cartry, J., Vogler, G., Mohapatra, B., ... Bodmer, R. (2011). Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. Journal of Cell Biology, 193(7), 1181-1196. https://doi.org/10.1083/jcb.201006114

Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. / Qian, Li; Wythe, Joshua D.; Liu, Jiandong; Cartry, Jerome; Vogler, Georg; Mohapatra, Bhagyalaxmi; Otway, Robyn T.; Huang, Yu; King, Isabelle N.; Maillet, Marjorie; Zheng, Yi; Crawley, Timothy; Taghli-Lamallem, Ouarda; Semsarian, Christopher; Dunwoodie, Sally; Winlaw, David; Harvey, Richard P.; Fatkin, Diane; Towbin, Jeffrey; Molkentin, Jeffery D.; Srivastava, Deepak; Ocorr, Karen; Bruneau, Benoit G.; Bodmer, Rolf.

In: Journal of Cell Biology, Vol. 193, No. 7, 27.06.2011, p. 1181-1196.

Research output: Contribution to journalArticle

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, J, Molkentin, JD, Srivastava, D, Ocorr, K, Bruneau, BG & Bodmer, R 2011, 'Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species', Journal of Cell Biology, vol. 193, no. 7, pp. 1181-1196. https://doi.org/10.1083/jcb.201006114
Qian, Li ; Wythe, Joshua D. ; Liu, Jiandong ; Cartry, Jerome ; Vogler, Georg ; Mohapatra, Bhagyalaxmi ; Otway, Robyn T. ; Huang, Yu ; King, Isabelle N. ; Maillet, Marjorie ; Zheng, Yi ; Crawley, Timothy ; Taghli-Lamallem, Ouarda ; Semsarian, Christopher ; Dunwoodie, Sally ; Winlaw, David ; Harvey, Richard P. ; Fatkin, Diane ; Towbin, Jeffrey ; Molkentin, Jeffery D. ; Srivastava, Deepak ; Ocorr, Karen ; Bruneau, Benoit G. ; Bodmer, Rolf. / Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. In: Journal of Cell Biology. 2011 ; Vol. 193, No. 7. pp. 1181-1196.
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