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

Development and Aging Program, NASCR Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2011; 193(7):1181-96. DOI: 10.1083/jcb.201006114
Source: PubMed


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.

Download full-text


Available from: Christopher Semsarian
  • Source
    • "Our previous data reveals that the mRNA level of Nkx2.5 is significantly increased after HBCD exposure in zebrafish [6]. miR-1 is negatively regulated by Nkx2.5 in cardiomyocytes to regulate heart function [25]. Therefore, the purpose of this study was to examine: (i) whether the expression of cardiovascular-related miR- NAs (especially miR-1) is changed after exposure to HBCD; (ii) whether up-regulated Nkx2.5 can directly repress miR-1 expression and then induce the dysfunctions of target genes; and (iii) whether and how cardiac hypertrophy and arrhythmia are affected by Nkx2.5 and miR-1 after treatment of zebrafish embryos with HBCD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hexabromocyclododecane (HBCD) is one of the most widely used brominated flame retardants. Although studies have reported that HBCD can cause a wide range of toxic effects on animals including humans, limited information can be found about its cardiac toxicity. In the present study, zebrafish embryos were exposed to HBCD at low concentrations of 0, 2, 20 and 200nM. The results showed that HBCD exposure could induce cardiac hypertrophy and increased deposition of collagen. In addition, disordered calcium (Ca(2+)) handling was observed in H9C2 rat cardiomyocyte cells exposed to HBCD. Using small RNA sequencing and real-time quantitative PCR, HBCD exposure was shown to induce significant changes in the miRNA expression profile associated with the cardiovascular system. Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells.
    Full-text · Article · Oct 2015 · Journal of hazardous materials
  • Source
    • "(2) Inhibition of ROCK, F2, or other key proteins in the RAF-MEK-ERK signaling caused dysfunction of actomyosin assembly contraction and later cardiac arrhythmias (Rose et al., 2010). (3) Inhibition of Cdc42, Rac or their upstream proteins caused dysfunction of MAPK signaling (Qian et al., 2011). This also served as a common mechanism in CDs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing.
    Full-text · Article · Oct 2013 · Toxicology and Applied Pharmacology
  • Source
    • "Because developmental networks are inherently dynamic, temporal control over molecular manipulations (e.g., gene knockdowns) and gene expression profiling with high temporal resolution are also important. Transcriptional networks are, of course, only a starting point and one may envision integrating such networks with the complex suite of epigenetic and post-transcriptional mechanisms that regulate gene expression (Qian et al., 2011; Gagan et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A central challenge of developmental and evolutionary biology is to explain how anatomy is encoded in the genome. Anatomy emerges progressively during embryonic development, as a consequence of morphogenetic processes. The specialized properties of embryonic cells and tissues that drive morphogenesis, like other specialized properties of cells, arise as a consequence of differential gene expression. Recently, gene regulatory networks (GRNs) have proven to be powerful conceptual and experimental tools for analyzing the genetic control and evolution of developmental processes. A major current goal is to link these transcriptional networks directly to morphogenetic processes. This review highlights three experimental models (sea urchin skeletogenesis, ascidian notochord morphogenesis, and the formation of somatic muscles in Drosophila) that are currently being used to analyze the genetic control of anatomy by integrating information of several important kinds: 1) morphogenetic mechanisms at the molecular, cellular and tissue levels that are responsible for shaping a specific anatomical feature, 2) the underlying GRN circuitry deployed in the relevant cells, and 3) modifications to gene regulatory circuitry that have accompanied evolutionary changes in the anatomical feature. © 2013 Wiley Periodicals, Inc.
    Preview · Article · Jun 2013 · genesis
Show more