Reduction of XNkx2-10 expression leads to anterior defects and malformation of the embryonic heart

Allen, Bryan G.; Allen‐Brady, Kristina; Weeks, Daniel L.

doi:10.1016/j.mod.2006.07.008

Cited by 7 publications

(9 citation statements)

References 25 publications

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“…A similar nkx2–5 dose-dependent increase in heart size was reported using zebra fish [10], although reduction in heart size and morphologic defects with further increases in nkx2–5 levels also has been reported [39]. Overexpression of Xenopus nkx2–10 has no obvious cardiac effect [3, 31]. …”

Section: Assays On the Trio Of Cardiac Nk-2 Genes In Xenopussupporting

confidence: 56%

“…However, in frog and chicken, it joins nkx2–5 and nkx2–10 (or Nkx2–8 in chicken) among NK-2 genes expressed in the heart. Although initial studies of nkx2–10 suggested that it was transiently expressed during early cardiac development [31, 37], a more recent analysis suggests that after a transient decrease, expression returns [3]. All the Xenopus cardiac NK-2 genes can be found in RNA isolated from adult heart, liver, and gut.…”

Section: Assays On the Trio Of Cardiac Nk-2 Genes In Xenopusmentioning

confidence: 99%

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Examining the Cardiac NK-2 Genes in Early Heart Development

2009

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The cardiac NK-2 transcription factors are the vertebrate relatives of the Drosophila tinman gene. Without the Drosophila tinman gene, fruit flies fail to form their heart ("dorsal vessel"), and mutations or altered expression of cardiac NK-2 genes may lead to abnormal heart formation in vertebrates. Although the cardiac NK-2 gene NKX2-5 is recognized as an important factor in cases of human congenital heart disease and heart development in vertebrates, the roles of the other cardiac NK-2 genes are less clear. This report reviews what is known about the cardiac NK-2 genes in cardiac development, comparing studies in several different model systems. KeywordsAbnormal heart formation; Cardiac NK-2 genes; Cardiac NK-2 transcription factors; Congenital heart disease; Early heart development One of the molecules critical to normal cardiac development across vertebrate species is the transcription factor Nkx2-5. Nkx2-5 is a member of a family of transcription factors that uses the Drosophila tinman protein, essential for dorsal vessel (the heart of the fly) formation in the fly, as a prototype. Mutations in NKX2-5 are among the most common genetic causes of nonsyndromic congenital heart disease in humans, and this homeodomain-containing transcription factor has been central to models of cardiac development.This review aims to introduce Nkx2-5 and closely related proteins expressed in cardiac tissue. Although studies investigating a variety of organisms are discussed, we highlight studies examining this family of proteins that have used embryos of the South African clawed frog, Xenopus laevis.

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Section: Assays On the Trio Of Cardiac Nk-2 Genes In Xenopussupporting

confidence: 56%

Section: Assays On the Trio Of Cardiac Nk-2 Genes In Xenopusmentioning

confidence: 99%

Examining the Cardiac NK-2 Genes in Early Heart Development

2009

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“…But, following initiation of cardiac differentiation markers, XNkx2-10 transcipts fade in the heart and remain abundant in the pharyngeal endoderm (Chambers et al, 1994; Drysdale et al, 1994). Interestingly, reduction of XNkx2-10 leads to anterior and cardiac defects during later stages of development, following looping and chamber emergence (Allen et al, 2006). Notably, the XNkx2-10 protein is more similar in length and its homeodomain is most identical to zebrafish Nkx2.7 than to the other Xenopus homologs, XNkx2-5 and XNkx2-3 (Newman et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood

George

Colombo

Targoff

2015

Developmental Biology

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Temporally controlled mechanisms that define the unique features of ventricular and atrial cardiomyocyte identity are essential for the construction of a coordinated, morphologically intact heart. We have previously demonstrated an important role for nkx genes in maintaining ventricular identity, however, the specific timing of nkx2.5 function in distinct cardiomyocyte populations has yet to be elucidated. Here, we show that heat-shock induction of a novel transgenic line, Tg(hsp70l:nkx2.5-EGFP), during the initial stages of cardiomyocyte differentiation leads to rescue of chamber shape and identity in nkx2.5−/− embryos as chambers emerge. Intriguingly, our findings link an early role of this essential cardiac transcription factor with a later function. Moreover, these data reveal that nkx2.5 is also required in the second heart field as the heart tube forms, reflecting the temporal delay in differentiation of this population. Thus, our results support a model in which nkx genes induce downstream targets that are necessary to maintain chamber-specific identity in both early- and late-differentiating cardiomyocytes at discrete stages in cardiac morphogenesis. Furthermore, we show that overexpression of nkx2.5 during first and second heart field development not only rescues the mutant phenotype, but also is sufficient for proper function of the adult heart. Taken together, these results shed new light on the stage-dependent mechanisms that sculpt chamber-specific cardiomyocytes and, therefore, have the potential to improve in vitro generation of ventricular cells to treat myocardial infarction and congenital heart disease.

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“…Nkx2-5 +/− mice and mice carrying a hypomorphic Nkx2-5 allele exhibit less dramatic morphogenetic defects, resembling the variety of phenotypes associated with NKX2-5 mutations in patients (Biben et al, 2000; Prall et al, 2007; Stanley et al, 2002). Additional studies in Xenopus further illuminate morphogenetic functions for NKX2-5 homologs: reduction of XNkx2-10 leads to the formation of a small ventricle with impaired trabeculation (Allen et al, 2006), and expression of versions of XNkx2-5 carrying CHD-associated mutations results in problems with atrial septation, atrioventricular valve formation, and cardiac conduction (Bartlett et al, 2007). Together, these data identify a myriad of important roles for NKX2-5 -related genes during cardiac morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number

Targoff

Schell

Yelon

2008

Developmental Biology

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Heart formation is a complex morphogenetic process, and perturbations in cardiac morphogenesis lead to congenital heart disease. NKX2-5 is a key causative gene associated with cardiac birth defects, presumably because of its essential roles during the early steps of cardiogenesis. Previous studies in model organisms implicate NKX2-5 homologs in numerous processes, including cardiac progenitor specification, progenitor proliferation, and chamber morphogenesis. By inhibiting function of the zebrafish NKX2-5 homologs, nkx2.5 and nkx2.7, we show that nkx genes are essential to establish the original dimensions of the linear heart tube. The nkx-deficient heart tube fails to elongate normally: its ventricular portion is atypically short and wide, and its atrial portion is disorganized and sprawling. This atrial phenotype is associated with a surplus of atrial cardiomyocytes, whereas ventricular cell number is normal at this stage. However, ventricular cell number is decreased in nkx-deficient embryos later in development, when cardiac chambers are emerging. Thus, we conclude that nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number. Our data suggest that morphogenetic errors could originate during early stages of heart tube assembly in patients with NKX2-5 mutations.

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Reduction of XNkx2-10 expression leads to anterior defects and malformation of the embryonic heart

Cited by 7 publications

References 25 publications

Examining the Cardiac NK-2 Genes in Early Heart Development

Examining the Cardiac NK-2 Genes in Early Heart Development

An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood

Nkx genes regulate heart tube extension and exert differential effects on ventricular and atrial cell number

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