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Exposure to Ethanol Leads to Midfacial Hypoplasia in a Zebrafish Model of FASD Via Indirect Interactions with the Shh Pathway Alfire Sidik1* , Groves Dixon2, Desire M

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Exposure to Ethanol Leads to Midfacial Hypoplasia in a Zebrafish Model of FASD Via Indirect Interactions with the Shh Pathway Alfire Sidik1* , Groves Dixon2, Desire M Sidik et al. BMC Biology (2021) 19:134 https://doi.org/10.1186/s12915-021-01062-9 RESEARCH ARTICLE Open Access Exposure to ethanol leads to midfacial hypoplasia in a zebrafish model of FASD via indirect interactions with the Shh pathway Alfire Sidik1* , Groves Dixon2, Desire M. Buckley1, Hannah G. Kirby1, Shuge Sun1 and Johann K. Eberhart1 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. * Correspondence: [email protected] 1Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Institute for Neuroscience, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas 78712, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sidik et al. BMC Biology (2021) 19:134 Page 2 of 18 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. Keywords: Wnt/planar cell polarity (PCP) pathway, Convergent extension, Vangl2, Sonic Hedgehog (Shh), Fetal alcohol spectrum disorders (FASD), Ethanol, Cyclopia, Polarity, Gastrulation Background the phenotypic expressivity of this trait varies with fac- Birth defects manifest as structural or functional malfor- tors such as temperature and genetic background [15]. mations at birth and are the leading cause of infant mor- In the screen, all untreated vangl2 mutants displayed tality in the USA [1]. Although the multifactorial proper separation of the eyes and craniofacial skeletal el- etiologies of birth defects are not well understood, many ements were intact [13]. Upon exposure to 1% ethanol, a are thought to derive from a complex interplay between dose that does not normally cause facial defects, vangl2 genetic and environmental factors. The adverse effects mutants were fully penetrant for cyclopia and displayed of teratogens, or environmental agents that cause irre- profound defects to the midfacial skeleton [13]. Ethanol- versible developmental defects, were first recognized in treated vangl2 heterozygotes were largely indistinguish- the 1950s and 1960s [2]. It was then that investigators able from their wild-type siblings, with the exception of began to observe developmental anomalies in infants ex- a single synophthalmic ethanol-treated heterozygote, posed to methylmercury and thalidomide in utero [3, 4]. providing evidence for latent haploinsufficiency. To- Since then, other environmental teratogens have come gether, these data suggest a synergistic interaction be- to light, including but not limited to, pollutants, pharma- tween a mutation in vangl2 and ethanol. ceuticals, and chemicals. We know vangl2 plays a critical role in mediating con- Prenatal alcohol exposure (PAE) is the most common vergent extension movements as evidenced by their body preventable cause of birth defects, yet the prevalence of axis defect; however, because the early effects of ethanol fetal alcohol spectrum disorders (FASD) in the USA is exposure remain poorly defined, the precise mechanism as high as 2–5% [5]. Fetal alcohol syndrome (FAS) is the of the vangl2-ethanol interaction remain elusive. To bet- most severe outcome following PAE and is characterized ter understand how ethanol interacts with loss of vangl2 by midfacial hypoplasia, as well as growth and neural to alter phenotypic outcomes, we took an unbiased ap- deficits [6]. While PAE is required for the development proach to assess the transcriptional response to ethanol. of FASD, the teratogenic effects of ethanol are modu- We performed single embryo RNA sequencing (RNA- lated by genetics [7, 8]. For instance, monozygotic twins seq) on control (untreated) and ethanol-treated wild- were 100% concordant for FAS, whereas dizygotic twins type embryos in a time-course spanning gastrulation and were only 63% concordant [8, 9]. Furthermore, animal early segmentation stages in zebrafish. models of FAS show strain-specific differences after con- Bioinformatic and functional analyses indicated that trolling for environmental variables such as dose and midfacial defects in ethanol-exposed vangl2 mutants timing [10, 11]. Despite this, the genetic factors that pro- were likely due to an indirect interaction between etha- tect or predispose an individual to FASD are poorly nol and the Shh pathway. While there was no alteration understood. Moreover, we still lack a basic understand- in the level of expression of direct Shh targets, a critical ing of the mechanism of ethanol teratogenesis. Zebrafish source of Shh signaling that separates the developing eye are well suited to address this problem due to their gen- field into bilateral eyes becomes mispositioned in etic tractability and ease of embryological manipulation ethanol-exposed embryos. We demonstrate that ethanol [12]. and loss of vangl2, synergistically interact to disrupt po- In a screen to identify genetic modifiers of ethanol larized cellular protrusions required for proper conver- teratogenicity, vang-like 2 (vangl2), a member of the gent extension movements. non-canonical Wnt/planar cell polarity (Wnt/PCP) path- way, emerged as an ethanol sensitive locus [13]. In zeb- Results rafish, mutations in the vangl2 locus disrupt convergent Early embryogenesis is the sensitive time window for extension movements during gastrulation, resulting in a vangl2 mutants shortened, broadened body axis [14]. These mutants can To determine the critical time window of ethanol sensi- present with cyclopia, a fusion of the bilateral eyes, but tivity for vangl2 mutants and heterozygotes, we first Sidik et al. BMC Biology (2021) 19:134 Page 3 of 18 initiated ethanol treatment at various stages comprising mechanism in vangl2 heterozygotes, as zygotic gene ex- late blastula to early gastrula for 24 h. The inner lens-to- pression initiates after high stage (4 hpf) in zebrafish. lens width was used as a measure of synophthalmia, and we calculated the occurrence of cyclopia to characterize The effect of ethanol on the early zebrafish transcriptome ethanol-induced teratogenesis. In control conditions, the is subtle relative to the developmental age spacing of the eyes in
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