Tinman/Nkx2-5 Acts Via MiR-1 and Upstream of Cdc42 to Regulate Heart Function Across Species

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2011 Jun 22

PMID 21690310

Citations 41

Authors

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 A Towbin

Jeffery D Molkentin

Deepak Srivastava

Karen Ocorr

Benoit G Bruneau

Rolf Bodmer

Affiliations

Soon will be listed here.

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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