Alcohol‐mediated calcium signals dysregulate pro‐survival Snai2/PUMA/Bcl2 networks to promote p53‐mediated apoptosis in avian neural crest progenitors

Flentke, George R.; Baulch, Joshua W.; Berres, Mark E.; Garic, Ana; Smith, Susan

doi:10.1002/bdr2.1508

Cited by 17 publications

(26 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, miR-3064 has inhibitory interactions with mRNA encoding human telomerase reverse transcriptase, or hTERT [42], which promotes cell invasion by upregulating Snai2. Alcohol induces Snai2 in these cells to accelerate their epithelial-mesenchymal transformation [43], and the reduced miR-3064 observed here suggests a mechanism that might explain this response. Although these miRNAs have not been specifically linked to facial morphogenesis, their presence suggests an alternate means by which their domicile genes could influence cranial development.…”

Section: Discussionmentioning

confidence: 92%

Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder

et al. 2019

Self Cite

View full text Add to dashboard Cite

Gestational alcohol exposure causes fetal alcohol spectrum disorder (FASD) and is a prominent cause of neurodevelopmental disability. Whole transcriptome sequencing (RNA-Seq) offer insights into mechanisms underlying FASD, but gene-level analysis provides limited information regarding complex transcriptional processes such as alternative splicing and non-coding RNAs. Moreover, traditional analytical approaches that use multiple hypothesis testing with a false discovery rate adjustment prioritize genes based on an adjusted p-value, which is not always biologically relevant. We address these limitations with a novel approach and implemented an unsupervised machine learning model, which we applied to an exon-level analysis to reduce data complexity to the most likely functionally relevant exons, without loss of novel information. This was performed on an RNA-Seq paired-end dataset derived from alcohol-exposed neural fold-stage chick crania, wherein alcohol causes facial deficits recapitulating those of FASD. A principal component analysis along with k-means clustering was utilized to extract exons that deviated from baseline expression. This identified 6857 differentially expressed exons representing 1251 geneIDs; 391 of these genes were identified in a prior gene-level analysis of this dataset. It also identified exons encoding 23 microRNAs (miRNAs) having significantly differential expression profiles in response to alcohol. We developed an RDAVID pipeline to identify KEGG pathways represented by these exons, and separately identified predicted KEGG pathways targeted by these miRNAs. Several of these (ribosome biogenesis, oxidative phosphorylation) were identified in our prior gene-level analysis. Other pathways are crucial to facial morphogenesis and represent both novel (focal adhesion, FoxO signaling, insulin signaling) and known (Wnt signaling) alcohol targets. Importantly, there was substantial overlap between the exomes themselves and the predicted miRNA targets, suggesting these miRNAs contribute to the gene-level expression changes. Our novel application of unsupervised machine learning in conjunction with statistical analyses facilitated the discovery of signaling pathways and miRNAs that inform mechanisms underlying FASD.

show abstract

Section: Discussionmentioning

confidence: 92%

Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, maternal alcohol drinking from GD 6 to GD 16, increased Tp53 expression in fetal cortices (Kuhn & Miller, 1998); but lower levels were found following maternal alcohol drinking from GD 10 to GD 13 (Hicks & Miller, 2019). Studies on the neural crest, which develops just after gastrulation, find that alcohol increases protein levels of Tp53 (Flentke et al, 2019) and Tp53-mediated apoptosis (Chen et al, 2015) and that blocking the transcriptional pathway induced by Tp53 can prevent apoptosis in specific regions (Flentke et al, 2019). Likewise, in a neuronal stem cell model, Tp53 gene knockdown has also been shown to protect against apoptosis .…”

Section: Discussionmentioning

confidence: 98%

“…Tp53 is activated by a number of biochemical signals including oxidative stress, DNA damage, and glucose deprivation. Importantly, these signals can be elicited by exposure to many developmental insults, such as radiation (Komarov et al, 1999), hyperthermia (Hosako et al, 2007), nutrient deficiency (Li et al, 2018), hydroxyurea (El Husseini & Hales, 2018b), benzopyrenes (Nicol et al, 1995), and alcohol (Anthony et al, 2008;Flentke et al, 2019;Ignacio et al, 2014;Kuhn & Miller, 1998). Studies examining teratogenesis in Tp53 knockout mice reveal the complex roles of Tp53 in the embryo.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have demonstrated that prenatal alcohol exposure (PAE) can induce Tp53 expression (Kuhn & Miller, 1998) and that shortly after gastrulation, neural crest cell apoptosis depends on Tp53 (Chen et al, 2015;Flentke et al, 2019;Rinon et al, 2011;Yuan et al, 2017), but studies have yet to elucidate the role of Tp53 in gastrulation stage apoptosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of tumor protein 53 protects against alcohol‐induced facial malformations in mice and zebrafish

Fish

Tucker²,

Peterson

et al. 2021

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background: Alcohol exposure during the gastrulation stage of development causes the craniofacial and brain malformations that define fetal alcohol syndrome. These malformations, such as a deficient philtrum, are exemplified by a loss of midline tissue and correspond, at least in part, to regionally selective cell death in the embryo. The tumor suppressor protein Tp53 is an important mechanism for cell death, but the role of Tp53 in the consequences of alcohol exposure during the gastrulation stage has yet to be examined. The current studies used mice and zebrafish to test whether genetic loss of Tp53 is a conserved mechanism to protect against the effects of early developmental stage alcohol exposure.Methods: Female mice, heterozygous for a mutation in the Tp53 gene, were mated with Tp53 heterozygous males, and the resulting embryos were exposed during gastrulation on gestational day 7 (GD 7) to alcohol (two maternal injections of 2.9 g/ kg, i.p., 4 h apart) or a vehicle control. Zebrafish mutants or heterozygotes for the tp53 zdf1 M214K mutation and their wild-type controls were exposed to alcohol (1.5% or 2%) beginning 6 h postfertilization (hpf), the onset of gastrulation.Results: Examination of GD 17 mice revealed that eye defects were the most common phenotype among alcohol-exposed fetuses, occurring in nearly 75% of the alcoholexposed wild-type fetuses. Tp53 gene deletion reduced the incidence of eye defects in both the heterozygous and mutant fetuses (to about 35% and 20% of fetuses, respectively) and completely protected against alcohol-induced facial malformations. Zebrafish (4 days postfertilization) also demonstrated alcohol-induced reductions of eye size and trabeculae length that were less common and less severe in tp53 mutants, indicating a protective effect of tp53 deletion.Conclusions: These results identify an evolutionarily conserved role of Tp53 as a pathogenic mechanism for alcohol-induced teratogenesis.

show abstract

“…This apoptotic process occurs due to an increase in the concentration of intracellular calcium (Garic, Flentke, Amberger, Hernandez, & Smith, ) which uncouples the Snai2/p53 regulation acting to prevent apoptosis during EMT in chick NCCs. Alcohol also increases snai2 and p53 expression in NCCs, represses bcl2 and blocks the PUMA induction, while ATM and PTEN levels are elevated (Flentke, Baulch, Berres, Garic, & Smith, ). It is noteworthy that these effects result from early alcohol exposure at low doses while the inhibitory action typically described for the effect of alcohol often used suprapharmacological doses for experimental exposure (Czarnobaj, Bagnall, Bamforth, & Milos, ; Hassler & Moran, ; Oyedele & Kramer, ; Rovasio & Battiato, ).…”

Section: Chemical Agentsmentioning

confidence: 99%

The role of teratogens in neural crest development

Cerrizuela

Vega-Lopez

Aybar

2020

Birth Defects Research

View full text Add to dashboard Cite

The neural crest (NC), discovered by Wilhelm His 150 years ago, gives rise to a multipotent migratory embryonic cell population that generates a remarkably diverse and important array of cell types during the development of the vertebrate embryo. These cells originate in the neural plate border (NPB), which is the ectoderm between the neural plate and the epidermis. They give rise to the neurons and glia of the peripheral nervous system, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies are a class of congenital diseases resulting from the abnormal induction, specification, migration, differentiation or death of NC cells (NCCs) during embryonic development and have an important medical and societal impact. In general, congenital defects affect an appreciable percentage of newborns worldwide. Some of these defects are caused by teratogens, which are agents that negatively impact the formation of tissues and organs during development. In this review, we will discuss the teratogens linked to the development of many birth defects, with a strong focus on those that specifically affect the development of the NC, thereby producing neurocristopathies.Although increasing attention is being paid to the effect of teratogens on embryonic development in general, there is a strong need to critically evaluate the specific role of these agents in NC development. Therefore, increased understanding of the role of these factors in NC development will contribute to the planning of strategies aimed at the prevention and treatment of human neurocristopathies, whose etiology was previously not considered.

show abstract

Alcohol‐mediated calcium signals dysregulate pro‐survival Snai2/PUMA/Bcl2 networks to promote p53‐mediated apoptosis in avian neural crest progenitors

Cited by 17 publications

References 66 publications

Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder

Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder

Loss of tumor protein 53 protects against alcohol‐induced facial malformations in mice and zebrafish

The role of teratogens in neural crest development

Contact Info

Product

Resources

About