Retinal Wnt signaling defect in a zebrafish fetal alcohol spectrum disorder model

Muralidharan, Pooja; Sarmah, Swapnalee

doi:10.1371/journal.pone.0201659

Cited by 14 publications

(16 citation statements)

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“…Notch signaling is important for neurogenesis and embryonic development through its influence on the expression of associated transcription factors, even in the adult brain [55]. Notch signaling has also been altered in prenatal alcohol exposure models involving mice [56] and zebrafish [57]. Our results further support the notion that MAPK and notch signaling, alongside other signaling cascades, implicate a role for altered transcriptional control in the adult hippocampus following prenatal alcohol exposure and early life stress.…”

Section: Discussionsupporting

confidence: 76%

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

Alberry

Castellani

Singh

2020

J Neurodevelop Disord

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Background: Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. Methods: We model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene coexpression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus. Results: We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e−12, p = 0.004, respectively). Conclusions: Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.

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Section: Discussionsupporting

confidence: 76%

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

Alberry

Castellani

Singh

2020

J Neurodevelop Disord

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“…Ethanol-induced dysregulation of retinoic acid signaling pathway was reported earlier 16,17,19,[38][39][40][41] . Our studies examining the heart and the eye in ethanol-treated embryos identified disruption of Wnt, Notch, retinoic acid and Bmp signaling pathways during organogenesis [17][18][19][20] . This study showed that those signaling defects initiate early in ethanol-exposed embryos and continue to have their detrimental effects at later stages of development.…”

Section: Discussionmentioning

confidence: 81%

“…However, developmental gene expression networks are highly conserved from fish to human 12 . Zebrafish is an established model for the study of embryonic ethanol-exposure effects on development and its functional consequences, providing insights into the potential mechanisms of ethanol teratogenicity [13][14][15] .Ethanol treatment of zebrafish embryos from 2 to 24 hours post-fertilization (hpf) reproducibly causes robust FASD-like defects, including craniofacial, cardiac, and neural defects [14][15][16][17][18][19][20][21] . This is a model for chronic ethanol exposure during early stages of pregnancy, when mothers may not know they are pregnant and may continue to drink alcohol.…”

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confidence: 99%

“…This is a model for chronic ethanol exposure during early stages of pregnancy, when mothers may not know they are pregnant and may continue to drink alcohol. Our previous studies provided evidence of critical signaling dysregulation during organogenesis, including BMP, Notch, Wnt, and retinoic acid, which leads to heart and eye defects 18,20 . Phenotypic differences between ethanol-treated and untreated embryos were first detected during gastrulation, when ethanol-treated embryos displayed reduced epiboly progression [22][23][24] .…”

mentioning

confidence: 99%

“…Ethanol treatment of zebrafish embryos from 2 to 24 hours post-fertilization (hpf) reproducibly causes robust FASD-like defects, including craniofacial, cardiac, and neural defects [14][15][16][17][18][19][20][21] . This is a model for chronic ethanol exposure during early stages of pregnancy, when mothers may not know they are pregnant and may continue to drink alcohol.…”

mentioning

confidence: 99%

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Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

Sarmah

Srivastava

McClintick

et al. 2020

Sci Rep

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Ethanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanoldysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.Fetal alcohol spectrum disorder (FASD) is caused by the exposure to ethanol during prenatal developmental 1-3 . FASD patients display a range of morphological deformities and neurological deficits, including characteristic craniofacial dysmorphology, cognitive impairment, sensory defects, motor disabilities and organ deformities. A recent meta-analysis of FASD among children and youth showed the prevalence is approximately 0.8% globally, but it exceeds 1% in 76 countries 4 . The World Health Organization (WHO) European Region has the highest prevalence of FASD (1.98%) followed by the WHO Region of Americas (0.88%) 4 . Among all the countries studied to date, FASD is the most prevalent in South Africa where the prevalence is as high as 11.1% 4 . FASD prevalence is notably higher among special populations, for example, low socioeconomic status populations 5,6 , children in orphanages, people in psychiatric care etc. 4 .Despite various proposed mechanisms to explain FASD etiology, the molecular targets of ethanol toxicity during development are poorly understood. Conception through gastrulation are sensitive periods for ethanol-induced defects 7,8 . During this period stem and progenitor cells transition from pluripotency to one of the three germ layers, and the cells undergo coordinated movements to organize the body plan 9,10 . These effects are regulated transcriptionally, for example, through the maternal to zygotic transition and the pluripotency transcriptional circuit. S...

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Zebrafish models of fetal alcohol spectrum disorders

Fernandes

Lovely

2021

Genesis

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Fetal alcohol spectrum disorder (FASD) describes a wide range of structural deficits and cognitive impairments. FASD impacts up to 5% of children born in the United States each year, making ethanol one of the most common teratogens. Due to limitations and ethical concerns, studies in humans are limited in their ability to study FASD. Animal models have proven critical in identifying and characterizing the mechanisms underlying FASD. In this review, we will focus on the attributes of zebrafish that make it a strong model in which to study ethanol‐induced developmental defects. Zebrafish have several attributes that make it an ideal model in which to study FASD. Zebrafish produced large numbers of externally fertilized, translucent embryos. With a high degree of genetic amenability, zebrafish are at the forefront of identifying and characterizing the gene‐ethanol interactions that underlie FASD. Work from multiple labs has shown that embryonic ethanol exposures result in defects in craniofacial, cardiac, ocular, and neural development. In addition to structural defects, ethanol‐induced cognitive and behavioral impairments have been studied in zebrafish. Building upon these studies, work has identified ethanol‐sensitive loci that underlie the developmental defects. However, analyses show there is still much to be learned of these gene‐ethanol interactions. The zebrafish is ideally suited to expand our understanding of gene‐ethanol interactions and their impact on FASD. Because of the conservation of gene function between zebrafish and humans, these studies will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

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Retinal Wnt signaling defect in a zebrafish fetal alcohol spectrum disorder model

Cited by 14 publications

References 81 publications

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder

Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

Zebrafish models of fetal alcohol spectrum disorders

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