Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Manisastry, Shyam M.; Han, Mingda; Linask, Kérsti K.

doi:10.1002/dvdy.20878

Cited by 39 publications

(41 citation statements)

References 71 publications

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“…The adverse effects of Ca channel blockade are similar to the effects that we reported previously with lithium ion exposure and with exogenous Wnt3A exposure [26]. All 3 branches of Wnt signaling pathways may be involved in heart organogenesis.…”

Section: Calcium and Cardiac Precursor Cell Differentiationsupporting

confidence: 83%

“…Wnt signaling early in gastrulation promotes cardiac differentiation [29]. If Wnt signaling, however, is potentiated into stages 4 and 5 of gastrulation, as by exogenous Wnt3A or LiCl exposure, it becomes inhibitory to cardiomyogenesis [26]. Normally, in the embryo Dickkopf-1 antagonizes canonical Wnt signaling to initiate differentiation [30].…”

Section: Calcium and Cardiac Precursor Cell Differentiationmentioning

confidence: 99%

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Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Linask¹,

Linask²

2010

Stem Cells and Development

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We suggest that characterization of processes involved in differentiation of the pluripotential cardiac precursor cells in their embryonic environment will permit identifying pathways important for induction of diverse stem cells toward the cardiac phenotype. Phenotypic characteristics of cardiac cells are their contractile and electrical properties. The objective of the present study was to define whether calcium (Ca þþ ) has a regulatory role in the pluripotential precursor cell population during commitment into cardiomyocytes. We used the chick embryo model because of ease of staging the embryos and visibility of heart development. Using the Ca þþ indicator Fluo-3=acetoxymethyl and confocal microscopy, we demonstrated the existence of higher free Ca þþ levels in the cardiogenic precursor cells than in neighboring cell populations outside of the heart fields. Subsequently, gastrulation stage 4=5 chick embryos were set up in modified New cultures in the medium containing either the L-type Ca channel blocker, diltiazem, or the N-type Ca channel inhibitor, x -conotoxin. The embryos were incubated for 22-24 h during which time the control embryos developed, beating looping hearts. At the end of incubation, exposure to the L-type channel blockade with diltiazem resulted in an inhibition of cardiomyogenesis in the most posterior, uncommitted, part of the heart fields. N-type channel blockade with x -conotoxin was less intense. Cells in the most anterior cardiogenic regions that were already committed at time of exposure continued to differentiate. Thus, regulation and maintenance of normal cytosolic Ca levels are necessary for the early steps of cardiomyocyte specification and commitment leading to differentiation.

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Section: Calcium and Cardiac Precursor Cell Differentiationsupporting

confidence: 83%

Section: Calcium and Cardiac Precursor Cell Differentiationmentioning

confidence: 99%

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Linask¹,

Linask²

2010

Stem Cells and Development

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“…Our experimental evidence, relating peak cardiac defects to an early timing of exposure during vertebrate gastrulation stages (Chen et al, 2008;Manisastry et al, 2006), means that the most susceptible exposure period for heart defects occurs before most women are aware they are pregnant. Moreover, evidence published since the mid-1990s suggests that the risk of birth defects arising from Li exposure during early pregnancy is high and can result in early embryonic lethality.…”

Section: Introductionmentioning

confidence: 94%

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Han

Serrano

Lastra-Vicente

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt–β-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt–β-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.

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“…Canonical Wnt signaling can have both positive and negative effects on cardiac specification and differentiation, dependent on the developmental stage when being induced (Manisastry et al, 2006;Verma and Lenka, 2010;Dohn and Waxman, 2012;Willems et al, 2011). Using the heat shock-inducible Wnt8 line Tg(hsp70:wnt8-gfp), we indeed observed that induction of Wnt8 at 16 hpf reduced the number of ventricular cardiomyocytes (supplementary material Fig.…”

Section: Loss Of Knypek/glypican4 Results In Reduced Cardiomyocyte Numentioning

confidence: 81%

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

2015

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Glypicans are heparan sulphate proteoglycans (HSPGs) attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, and interact with various extracellular growth factors and receptors. The Drosophila division abnormal delayed (dally) was the first glypican lossof-function mutant described that displays disrupted cell divisions in the eye and morphological defects in the wing. In human, as in most vertebrates, six glypican-encoding genes have been identified (GPC1-6), and mutations in several glypican genes cause multiple malformations including congenital heart defects. To understand better the role of glypicans during heart development, we studied the zebrafish knypek mutant, which is deficient for Gpc4. Our results demonstrate that knypek/gpc4 mutant embryos display severe cardiac defects, most apparent by a strong reduction in cardiomyocyte numbers. Cell-tracing experiments, using photoconvertable fluorescent proteins and genetic labeling, demonstrate that Gpc4 'Knypek' is required for specification of cardiac progenitor cells and their differentiation into cardiomyocytes. Mechanistically, we show that Bmp signaling is enhanced in the anterior lateral plate mesoderm of knypek/gpc4 mutants and that genetic inhibition of Bmp signaling rescues the cardiomyocyte differentiation defect observed in knypek/gpc4 embryos. In addition, canonical Wnt signaling is upregulated in knypek/gpc4 embryos, and inhibiting canonical Wnt signaling in knypek/gpc4 embryos by overexpression of the Wnt inhibitor Dkk1 restores normal cardiomyocyte numbers. Therefore, we conclude that Gpc4 is required to attenuate both canonical Wnt and Bmp signaling in the anterior lateral plate mesoderm to allow cardiac progenitor cells to specify and differentiate into cardiomyocytes. This provides a possible explanation for how congenital heart defects arise in glypican-deficient patients.

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Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Cited by 39 publications

References 71 publications

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

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