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

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

doi:10.1083/jcb.201006114

Cited by 75 publications

(73 citation statements)

References 72 publications

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“…It is possible that cdc42 gene expression is tightly regulated in Tin+ CBs in the developing DV. This idea is consistent with recent studies that showed that Cdc42 is an indirect target of Tin in the adult fly heart where it plays an important role in regulating heart function (Qian et al, 2011). Alternatively, Cdc42 activity may be preferentially up regulated in the Tin+ cells or down regulated in the Svp+.…”

Section: Discussionsupporting

confidence: 93%

Cdc42 is required in a genetically distinct subset of cardiac cells during Drosophila dorsal vessel closure

Swope

Kramer

King

et al. 2014

Developmental Biology

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The embryonic heart tube is formed by the migration and subsequent midline convergence of two bilateral heart fields. In Drosophila the heart fields are organized into two rows of cardioblasts (CBs). While morphogenesis of the dorsal ectoderm, which lies directly above the Drosophila dorsal vessel (DV), has been extensively characterized, the migration and concomitant fundamental factors facilitating DV formation remain poorly understood. Here we provide evidence that DV closure occurs at multiple independent points along the A-P axis of the embryo in a “buttoning” pattern, divergent from the zippering mechanism observed in the overlying epidermis during dorsal closure. Moreover, we demonstrate that a genetically distinct subset of CBs is programmed to make initial contact with the opposing row. To elucidate the cellular mechanisms underlying this process, we examined the role of Rho GTPases during cardiac migration using inhibitory and overexpression approaches. We found that Cdc42 shows striking cell-type specificity during DV formation. Disruption of Cdc42 function specifically prevents CBs that express the homeobox gene tinman from completing their dorsal migration, resulting in a failure to make connections with their partnering CBs. Conversely, neighboring CBs that express the orphan nuclear receptor, seven-up, are not sensitive to Cdc42 inhibition. Furthermore, this phenotype was specific to Cdc42 and was not observed upon perturbation of Rac or Rho function. Together with the observation that DV closure occurs through the initial contralateral pairing of tinman-expressing CBs, our studies suggest that the distinct buttoning mechanism we propose for DV closure is elaborated through signaling pathways regulating Cdc42 activity in this cell type.

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Section: Discussionsupporting

confidence: 93%

Cdc42 is required in a genetically distinct subset of cardiac cells during Drosophila dorsal vessel closure

Swope

Kramer

King

et al. 2014

Developmental Biology

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“…The third cluster, miR-206/miR-133, is expressed primarily in somites during skeletal muscle development. The miR-1/miR-133a clusters are regulated by several important myogenic transcription factors, including SRF, MEF2C, and NKX2-5 (99). Deletion of miR-1-2 causes lethality between E15.5 and birth, as a result of ventricular septal defects (146).…”

Section: Micrornas In Cardiac Developmentmentioning

confidence: 99%

Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine

Burridge

Sharma

2015

Annu. Rev. Genet.

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Regeneration or replacement of lost cardiomyocytes within the heart has the potential to revolutionize cardiovascular medicine. Numerous methodologies have been used to achieve this aim, including the engraftment of bone marrow- and heart-derived cells as well as the identification of modulators of adult cardiomyocyte proliferation. Recently, the conversion of human somatic cells into induced pluripotent stem cells and induced cardiomyocyte-like cells has transformed potential approaches toward this goal, and the engraftment of cardiac progenitors derived from human embryonic stem cells into patients is now feasible. Here we review recent advances in our understanding of the genetic and epigenetic control of human cardiogenesis, cardiac differentiation, and the induced reprogramming of somatic cells to cardiomyocytes. We also cover genetic programs for inducing the proliferation of endogenous cardiomyocytes and discuss the genetic state of cells used in cardiac regenerative medicine.

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“…Sequence analysis of this upstream fragment revealed conserved consensus response elements corresponding to the early cardiac determination transcription factor Nkx2-5. Accordingly, the fly transcription factor Tinman and its homologue Nkx2-5 in mice have been shown to regulate the expression of miR-1 by directly binding upstream-specific cis -regulatory response elements (Qian et al ., 2011). The Rho-GTPase CDC42 interacts with Tinman/Nkx2-5 and cooperates to regulate miR-1 expression; more interestingly, CDC42 itself is a miR-1 target.…”

Section: Mirnas In Cardiac Development Function and Diseasementioning

confidence: 99%

“…The Rho-GTPase CDC42 interacts with Tinman/Nkx2-5 and cooperates to regulate miR-1 expression; more interestingly, CDC42 itself is a miR-1 target. This feedback regulatory network is involved in cardiac output and the formation of a normal myofibrillar architecture (Qian et al ., 2011). Similarly, SRF, Mef2c, MyoD, and Myogenin have been shown to directly bind consensus-conserved response elements in order to regulate miR-1 expression in cardiac and skeletal muscle tissues (Liu et al ., 2007; Rao et al ., 2006).…”

Section: Mirnas In Cardiac Development Function and Diseasementioning

confidence: 99%

MicroRNAs in Heart Development

Espinoza‐Lewis

Wang

2012

Current Topics in Developmental Biology

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MicroRNAs (miRNAs) are a class of small noncoding RNAs of ~22 nt in length which are involved in the regulation of gene expression at the posttranscriptional level by degrading their target mRNAs and/or inhibiting their translation. Expressed ubiquitously or in a tissue-specific manner, miRNAs are involved in the regulation of many biological processes such as cell proliferation, differentiation, apoptosis, and the maintenance of normal cellular physiology. Many miRNAs are expressed in embryonic, postnatal, and adult hearts. Aberrant expression or genetic deletion of miRNAs is associated with abnormal cardiac cell differentiation, disruption of heart development, and cardiac dysfunction. This chapter will summarize the history, biogenesis, and processing of miRNAs as well as their function in heart development, remodeling, and disease.

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

Abstract: Cdc42 regulates cardiac function in mice and flies downstream of a conserved Tinman/Nkx2-5–miR-1 signaling network.

Cited by 75 publications

References 72 publications

Cdc42 is required in a genetically distinct subset of cardiac cells during Drosophila dorsal vessel closure

Cdc42 is required in a genetically distinct subset of cardiac cells during Drosophila dorsal vessel closure

Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine

MicroRNAs in Heart Development

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