Prenatal ethanol exposure phenocopies <i>Cdon</i> mutation by impeding Shh function in the etiology of optic nerve hypoplasia

Kahn, Benjamin; Corman, Tanya S.; Lovelace, Korah; Hong, Mingi; Krauss, Robert M.; Epstein, Douglas J.

doi:10.1242/dmm.026195

Cited by 27 publications

(19 citation statements)

References 66 publications

(108 reference statements)

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“…; Kahn et al . ). Accordingly, we found that most of the neural signaling molecules were affected as a result of EtOH treatment and the maximally dysregulated pathways were captured as bubble graph (Fig.…”

Section: Resultsmentioning

confidence: 97%

Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR‐145

Louis

Gopurappilly

Surendran

et al. 2017

Journal of Neurochemistry

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Gestational alcohol exposure causes a range of neuropsychological disorders by modulating neurodevelopmental genes and proteins. The extent of damage depends on the stage of the embryo as well as dosage, duration and frequency of exposure. Here, we investigated the neurotoxic effects of alcohol using human embryonic stem cells. Multiple read-outs were engaged to assess the proliferation and differentiation capacity of neural precursor cells upon exposure to 100 mM ethanol for 48 h corresponding to the blood alcohol levels for binge drinkers. Whole-genome analysis revealed a spatiotemporal dysregulation of neuronal- and glial-specific gene expression that play critical roles in central nervous system (CNS) development. Alterations observed in the transcriptome may be attributed to epigenetic constitution witnessed by differential histone H3 Lys-4/Lys-27 modifications and acetylation status. In-depth mRNA and protein expression studies revealed abrogated extracellular signal-regulated kinases signaling in alcohol-treated cells. Consistent with this finding, ingenuity pathway analysis and micro-RNA profiling demonstrated up-regulation of miR-145 by targeting the neural specifier Sox-2. We also show that the neurite branching complexity of tubulin, beta 3 class III+ neurons was greatly reduced in response to alcohol. Finally, in vivo studies using zebrafish embryos reconfirmed the in vitro findings. Employing molecular endpoints in a human model, this report indicates for the first time that acute alcohol exposure could lead to impaired brain development via perturbation of extracellular signal-regulated kinases pathway and miR-145. However, it still needs to be addressed whether these modulations sustain throughout development, compromising the ability of the individual during adulthood and aging.

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Section: Resultsmentioning

confidence: 97%

Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR‐145

Louis

Gopurappilly

Surendran

et al. 2017

Journal of Neurochemistry

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“…Sonic hedgehog signaling is essential for patterning and brain development [49]. Furthermore, prenatal ethanol exposure causes ONH by inhibition of sonic hedgehog signaling in retinal progenitor cells in mice, resulting in failure to extend axons to the optic nerve [50]. Accordingly, both genetic and environmental factors may affect the sonic hedgehog signaling pathway and cause ONH.…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia

et al. 2020

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Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/ 29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.

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“…Similarly, ethanol exposure exacerbates defects in midline patterning and SHH signaling in 129S6 Cdo −/− mice (Hong & Krauss, 2012;Kahn et al, 2017). The precise mechanism by which ethanol perturbs SHH signaling remains unknown.…”

Section: Gene-environment Interactionsmentioning

confidence: 99%

Developmental processes regulate craniofacial variation in disease and evolution

Merkuri

Fish

2018

Genesis

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Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.

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Prenatal ethanol exposure phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia

Cited by 27 publications

References 66 publications

Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR‐145

Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR‐145

Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia

Developmental processes regulate craniofacial variation in disease and evolution

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