scholarly journals Prenatal alcohol exposure disrupts Shh pathway and primary cilia genes in the mouse neural tube

2019 ◽  
Author(s):  
Karen E. Boschen ◽  
Eric W. Fish ◽  
Scott E. Parnell
Keyword(s):  
Cell Cycle ◽  
Neural Tube ◽  
Primary Cilia ◽  
Alcohol Exposure ◽  
Brain Structures ◽  
Joubert Syndrome ◽  
Cell Cycle Gene ◽  
Layer Width ◽  
Shh Pathway ◽  
Prenatal Alcohol

AbstractNeurulation-stage alcohol exposure (NAE; embryonic day [E] 8-10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction. Female C57BL/6J mice were administered two doses of alcohol (2.9 g/kg/dose) or vehicle on E9. Embryos were collected 6, 12, or 24 hr later, and changes to Shh, cell cycle genes, and primary cilia were measured in the rostroventral neural tube (RVNT). Within the first 24 hours post-NAE, reductions in Shh pathway and cell cycle gene expression and the ratio of Gli3 forms in the full-length activator state were observed. RVNT volume and cell layer width were reduced at 12 hr. In addition, expression of multiple cilia-related genes were observed at 6 hr post-NAE. As a further test of cilia gene-ethanol interaction, mice heterozygous for Kif3a exhibited perturbed behavior during adolescence following NAE compared to vehicle-treated mice, and Kif3a heterozygosity exacerbated the hyperactive effects of NAE on exploratory activity. These data demonstrate that NAE downregulates the Shh pathway in a region of the neural tube that gives rise to alcohol-sensitive brain structures and identifies disruption of primary cilia function, or a “transient ciliopathy”, as a possible cellular mechanism of prenatal alcohol pathogenesis.

scholarly journals VP24.11: Prenatal alcohol exposure affects specific fetal brain structures: an atlas‐based fetal MRI study

2021 ◽  
Vol 58 (S1) ◽  
pp. 203-203
Author(s):  
M. Stuempflen ◽  
E. Schwartz ◽  
M.C. Diogo ◽  
S. Glatter ◽  
B. Pfeiler ◽  
...  
Keyword(s):  
Prenatal Alcohol Exposure ◽  
Fetal Brain ◽  
Fetal Mri ◽  
Alcohol Exposure ◽  
Brain Structures ◽  
Prenatal Alcohol ◽  
Mri Study

scholarly journals Gene-environment interactions characterized by single embryo transcriptomics

2019 ◽  
Author(s):  
Alfire Sidik ◽  
Groves B. Dixon ◽  
Hannah G. Kirby ◽  
Johann K. Eberhart
Keyword(s):  
Cell Polarity ◽  
Birth Defects ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Convergent Extension ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Gene Environment ◽  
Midfacial Hypoplasia ◽  
Prenatal Alcohol

AbstractGene-environment interactions are likely to underlie most human birth defects. The most common environmental contributor to birth defects is likely prenatal alcohol exposure. Fetal Alcohol Spectrum Disorders (FASD) describes the full range of defects that result from prenatal alcohol exposure. Gene-ethanol interactions underlie susceptibility to FASD but we lack a mechanistic understanding of these interactions. Here, we leverage the genetic tractability of zebrafish to address this problem. We first show that vangl2, a member of the Wnt/planar cell polarity (Wnt/PCP) pathway that mediates convergent extension movements, strongly interacts with ethanol during late blastula and early gastrula stages. Embryos mutant or heterozygous for vangl2 are sensitized to ethanol- induced midfacial hypoplasia. We performed single-embryo RNA-Seq during early embryonic stages, to assess individual variation to the transcriptional response to ethanol and determine the mechanism of the vangl2-ethanol interaction. To identify the pathway(s) that are disrupted by ethanol we used these global changes in gene expression to identify small molecules that mimic the effects of ethanol via the Library of Integrated Network- based Cellular Signatures (LINCS L1000) dataset. Surprisingly, this dataset predicted that the Sonic Hedgehog (Shh) pathway inhibitor, cyclopamine, would mimic the effects of ethanol, despite the fact that ethanol did not alter the expression levels of direct targets of Shh signaling. Indeed, we found that ethanol and cyclopamine strongly interact to disrupt midfacial development. Collectively, these results suggest that the midfacial defects in ethanol-exposed vangl2 mutants are due to an indirect interaction between ethanol and the Shh pathway. Vangl2 functions as part of a signaling pathway that regulates coordinated cell movements during midfacial development. Consistent with an indirect model, a critical source of Shh signaling that separates the developing eye field into bilateral eyes, allowing the expansion of the midface, becomes mispositioned in ethanol-exposed vangl2 mutants. We demonstrate that ethanol also interacts with another Wnt/PCP pathway member, gpc4, and a chemical inhibitor, blebbistatin. By characterizing membrane protrusions, we demonstrate that ethanol synergistically interacts with the loss of vangl2 to disrupt cell polarity required for convergent extension movements. Collectively, our results shed light on the mechanism by which the most common teratogen can disrupt development.

scholarly journals Exposure to ethanol leads to midfacial hypoplasia in a zebrafish model of FASD via indirect interactions with the Shh pathway

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Alfire Sidik ◽  
Groves Dixon ◽  
Desire M. Buckley ◽  
Hannah G. Kirby ◽  
Shuge Sun ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Birth Defects ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Global Changes ◽  
Convergent Extension ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Midfacial Hypoplasia ◽  
Prenatal Alcohol

Abstract Background Gene-environment interactions are likely to underlie most human birth defects. The most common known environmental contributor to birth defects is prenatal alcohol exposure. Fetal alcohol spectrum disorders (FASD) describe the full range of defects that result from prenatal alcohol exposure. Gene-ethanol interactions underlie susceptibility to FASD, but we lack a mechanistic understanding of these interactions. Here, we leverage the genetic tractability of zebrafish to address this problem. Results We first show that vangl2, a member of the Wnt/planar cell polarity (Wnt/PCP) pathway that mediates convergent extension movements, strongly interacts with ethanol during late blastula and early gastrula stages. Embryos mutant or heterozygous for vangl2 are sensitized to ethanol-induced midfacial hypoplasia. We performed single-embryo RNA-seq during early embryonic stages to assess individual variation in the transcriptional response to ethanol and determine the mechanism of the vangl2-ethanol interaction. To identify the pathway(s) that are disrupted by ethanol, we used these global changes in gene expression to identify small molecules that mimic the effects of ethanol via the Library of Integrated Network-based Cellular Signatures (LINCS L1000) dataset. Surprisingly, this dataset predicted that the Sonic Hedgehog (Shh) pathway inhibitor, cyclopamine, would mimic the effects of ethanol, despite ethanol not altering the expression levels of direct targets of Shh signaling. Indeed, we found that ethanol and cyclopamine strongly, but indirectly, interact to disrupt midfacial development. Ethanol also interacts with another Wnt/PCP pathway member, gpc4, and a chemical inhibitor of the Wnt/PCP pathway, blebbistatin, phenocopies the effect of ethanol. By characterizing membrane protrusions, we demonstrate that ethanol synergistically interacts with the loss of vangl2 to disrupt cell polarity required for convergent extension movements. Conclusions Our results show that the midfacial defects in ethanol-exposed vangl2 mutants are likely due to an indirect interaction between ethanol and the Shh pathway. Vangl2 functions as part of a signaling pathway that regulates coordinated cell movements during midfacial development. Ethanol exposure alters the position of a critical source of Shh signaling that separates the developing eye field into bilateral eyes, allowing the expansion of the midface. Collectively, our results shed light on the mechanism by which the most common teratogen can disrupt development.

Arsenic-induced neural tube defects in mice: Alterations in cell cycle gene expression

1996 ◽  
Vol 10 (6) ◽  
pp. 447-454 ◽  
Author(s):  
Bogdan J. Wlodarczyk ◽  
Gregory D. Bennett ◽  
Jim A. Calvin ◽  
Richard H. Finnell
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Cell Cycle Gene ◽  
Cell Cycle Gene Expression

Complex Trauma and Prenatal Alcohol Exposure: Clinical Implications

2012 ◽  
Vol 13 (2) ◽  
pp. 32-42 ◽  
Author(s):  
Yvette D. Hyter
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Child Development ◽  
Academic Outcomes ◽  
Complex Trauma ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Clinical Implications ◽  
Prenatal Alcohol ◽  
The Brain

Abstract Complex trauma resulting from chronic maltreatment and prenatal alcohol exposure can significantly affect child development and academic outcomes. Children with histories of maltreatment and those with prenatal alcohol exposure exhibit remarkably similar central nervous system impairments. In this article, I will review the effects of each on the brain and discuss clinical implications for these populations of children.

Prenatal alcohol exposure and signs of minor neurological dysfunction at preschool age

2000 ◽  
Vol 42 (8) ◽  
pp. 508-514 ◽  
Author(s):  
Béatrice Larroque ◽  
Monique Kaminski ◽  
Phillipe Dehaene ◽  
Damien Subtil ◽  
Denis Querleu
Keyword(s):  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Preschool Age ◽  
Neurological Dysfunction ◽  
Minor Neurological Dysfunction ◽  
Prenatal Alcohol

Impact of Moderate Prenatal Alcohol Exposure on Problem Behaviors in Preschool and School Children

2014 ◽  
Vol 46 (2) ◽  
pp. 89-100 ◽  
Author(s):  
Manuela Pfinder ◽  
Stefan Liebig ◽  
Reinhold Feldmann
Keyword(s):  
Problem Behaviors ◽  
Tobacco Smoke ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Smoke Exposure ◽  
Low Ses ◽  
German Health ◽  
Kiggs Study ◽  
Strengths And Difficulties ◽  
Prenatal Alcohol

Data on the relation between moderate prenatal alcohol exposure (PAE) and behavioral disorders are inconsistent, and this raises new questions. We examined (1) the association between moderate PAE and problem behaviors and (2) whether these associations differed by levels of socioeconomic status (SES), fetal smoke exposure, or exposure to environmental tobacco smoke (ETS). Data were taken from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study. Parents evaluated children’s behaviors using the Strengths and Difficulties Questionnaire (SDQ). Results showed a slight, but insignificant, increase of problem behaviors in children with moderate PAE. In 3- to 6-year-olds, PAE had a stronger effect on hyperactivity/inattention in combination with fetal smoke exposure (odds ratio = 2.82), than did PAE alone. Effects were not stronger in low-SES children, but they were stronger in children with ETS. We conclude that moderate PAE might have adverse effects on neurodevelopment, with stronger effects in disadvantaged populations. To confirm our preliminary findings, further research should be conducted.

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