Structural Constraints for Alcohol‐Stimulated Ca<sup>2+</sup> Release in Neural Crest, and Dual Agonist/Antagonist Properties of <i>n</i>‐Octanol

Garic-Stankovic, Ana; Hernandez, M. Rosario; Flentke, George R.; Smith, Susan

doi:10.1111/j.1530-0277.2005.00061.x

Cited by 24 publications

(34 citation statements)

References 47 publications

(75 reference statements)

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“…These sections were stained with hematoxylin and eosin and photographed at an original magnification of ϫ40 with a red filter to enhance contrast. Garic-Stankovic et al, 2006), and activity-induced, finely regulated gene induction by means of activated calcium channels also is important in other cells derived from the neural ectoderm (e.g., West et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Rosenquist

Bennett

Brauer

et al. 2007

Developmental Dynamics

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The amino acid homocysteine increases in the serum when there is insufficient folic acid or vitamin B 12 , or with certain mutations in enzymes important in methionine metabolism. Elevated homocysteine is related to increased risk for cardiovascular and other diseases in adults and elevated maternal homocysteine increases the risk for certain congenital defects, especially those that result from abnormal development of the neural crest and neural tube. Experiments with the avian embryo model have shown that elevated homocysteine perturbs neural crest/neural tube migration in vitro and in vivo. Whereas there have been numerous studies of homocysteine-induced changes in gene expression in adult cells, there is no previous report of a homocysteine-responsive transcriptome in the embryonic neural crest. We treated neural crest cells in vitro with exogenous homocysteine in a protocol that induces significant changes in neural crest cell migration. We used microarray analysis and expression profiling to identify 65 transcripts of genes of known function that were altered by homocysteine. The largest set of effected genes (19) included those with a role in cell migration and adhesion. Other major groups were genes involved in metabolism (13); DNA/RNA interaction (11); cell proliferation/apoptosis (10); and transporter/receptor (6). Although the genes identified in this experiment were consistent with prior observations of the effect of homocysteine upon neural crest cell function, none had been identified previously as response to homocysteine in adult cells.

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Section: Discussionmentioning

confidence: 99%

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Rosenquist

Bennett

Brauer

et al. 2007

Developmental Dynamics

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“…Those studies revealed that clinically relevant ethanol concentrations cause the rapid mobilization of intracellular calcium (Ca i +2 ) stores within the premigratory neural crest progenitors that reside in the dorsal neural folds (Debelak-Kragtorp et al 2003). We found that this Ca i +2 transient originates from ethanol’s activation of G protein-coupled signaling via Gα i2/3 and Gβγ (Garic-Stankovic et al 2005, 2006), which in turn activates phospholipase Cβ and phosphoinositide-mediated release of Ca i +2 stores. Chelators of intracellular calcium prevent both the ethanol-induced Ca i +2 rise and the resulting cell death (Debelak-Kragtorp et al 2003), thus normalizing neural crest survival.…”

Section: Introductionmentioning

confidence: 89%

“…For in ovo studies, saline or 0.43 mmol ethanol in isotonic saline was injected into the egg yolk center at stage 8/9; this produces a peak embryonic ethanol concentration of 50–60 mM for 1–1.5 hr (Debelak and Smith, 2000). Ex vivo studies incubated stage 8/9 embryos 2hr in Tyrode’s buffer ± 52 mM ethanol; this ethanol concentration causes half-maximal calcium release in these embryos (Garic-Stankovic et al 2006). Some embryos were pretreated with Bapta-AM (1 mM, 15 min) or ionomycin (50 μM, 5 min) prior to ethanol challenge.…”

Section: Methodsmentioning

confidence: 99%

Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome

Flentke

Garic

Amberger

et al. 2011

Birth Defects Research Part A: Clinical and Molecular Teratolog

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Fetal Alcohol Syndrome (FAS) is a common birth defect in many societies. Affected individuals have neurodevelopmental disabilities and a distinctive craniofacial dysmorphology. These latter deficits originate during early development from the ethanol-mediated apoptotic depletion of cranial facial progenitors, a population known as the neural crest. We showed previously that this apoptosis is caused because acute ethanol exposure activates a G protein-dependent intracellular calcium within cranial neural crest progenitors, and this calcium transient initiates the cell death. The dysregulated signals that reside downstream of ethanol’s calcium transient and effect neural crest death are unknown. Here we show that ethanol’s repression of the transcriptional effector β-catenin causes the neural crest losses. Clinically-relevant ethanol concentrations (22–78 mM) rapidly deplete nuclear β-catenin from neural crest progenitors, with accompanying losses of β-catenin transcriptional activity and downstream genes that govern neural crest induction, expansion and survival. Using forced expression studies we show that β-catenin loss of function (via dominant-negative TCF) recapitulates ethanol’s effects on neural crest apoptosis, whereas β-catenin gain-of-function in ethanol’s presence preserves neural crest survival. Blockade of ethanol’s calcium transient using Bapta-AM normalizes β-catenin activity and prevents the neural crest losses, whereas ionomycin treatment is sufficient to destabilize β-catenin. We propose that ethanol’s repression of β-catenin causes the neural crest losses in this model of FAS. β-Catenin is a novel target for ethanol’s teratogenicity. β-Catenin/Wnt signals participate in many developmental events and its rapid and persistent dysregulation by ethanol may explain why the latter is such a potent teratogen.

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“…Follow-up studies using genetic and small molecule approaches deciphered that the signaling mechanism underlying this alcohol-mediated apoptosis involve calcium-mediated Wnt signaling (Figure 1). Specifically, exposure of early neuroprogenitors including neural crest to pharmacologically-relevant alcohol levels (10 to 100 mM) invokes a calcium transient (EC50 = 52 mM), similar to its effect on oocytes, gastrulating mouse embryos, and placental trophoblasts (Debelak-Kragtorp et al 2003; Garic-Stankovic et al 2006). This calcium transient originates from a pertussis toxin-sensitive G protein-coupled receptor (Gαi/o) and inositidyl-phosphate signaling in a dose-dependent manner (Garic-Stankovic et al 2005) and activates the calmodulin-dependent protein kinase CaMKII (Garic et al 2011); blockade of these steps using either small-molecule or targeted misexpression approaches normalizes neural crest survival in alcohol’s presence.…”

Section: Mechanistic Insights From Avian Models Of Fasdmentioning

confidence: 99%

The avian embryo as a model for fetal alcohol spectrum disorder

Flentke

Smith

2018

Biochem. Cell Biol.

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Prenatal alcohol exposure (PAE) remains a leading preventable cause of structural birth defects and permanent neurodevelopmental disability. The chick (Gallus gallus domesticus) is a powerful embryological research model and was possibly the first (Fere, 1895) in which alcohol’s teratogenicity was demonstrated. Pharmacologically relevant alcohol exposures in the range of 20–70 mM (20–80 mg/egg) disrupt chick embryo growth, morphogenesis, and behavior, and the resulting phenotypes strongly parallel those of mammalian models. The avian embryo’s direct accessibility has enabled novel insights into alcohol’s teratogenic mechanisms. These include the contribution of IGF1 signaling to growth suppression, the altered flow dynamics that reshape valvuloseptal morphogenesis and mediate its cardiac teratogenicity, and the suppression of Wnt and Shh signals to disrupt neural crest migration, expansion, and survival and underlie its characteristic craniofacial deficits. The genetic diversity within commercial avian strains enabled identification of unique loci, such as ribosome biogenesis, that modify vulnerability to alcohol. This venerable research model is equally relevant for the future, as the application of technological advances including CRISPR, optogenetics, and biophotonics to the embryo’s ready accessibility creates a unique model in which investigators can manipulate and monitor the embryo in real-time to investigate alcohol’s actions upon cell fate.

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Structural Constraints for Alcohol‐Stimulated Ca²⁺ Release in Neural Crest, and Dual Agonist/Antagonist Properties of n‐Octanol

Cited by 24 publications

References 47 publications

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome

The avian embryo as a model for fetal alcohol spectrum disorder

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Structural Constraints for Alcohol‐Stimulated Ca2+ Release in Neural Crest, and Dual Agonist/Antagonist Properties of n‐Octanol

Cited by 24 publications

References 47 publications

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome

The avian embryo as a model for fetal alcohol spectrum disorder

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Structural Constraints for Alcohol‐Stimulated Ca²⁺ Release in Neural Crest, and Dual Agonist/Antagonist Properties of n‐Octanol