Neural crest development in fetal alcohol syndrome

Abstract

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability. Some affected individuals possess distinctive craniofacial deficits, but many more lack overt facial changes. An understanding of the mechanisms underlying these deficits would inform their diagnostic utility. Our understanding of these mechanisms is challenged because ethanol lacks a single receptor when redirecting cellular activity. This review summarizes our current understanding of how ethanol alters neural crest development. Ample evidence shows that ethanol causes the “classic” fetal alcohol syndrome (FAS) face (short palpebral fissures, elongated upper lip, deficient philtrum) because it suppresses prechordal plate outgrowth, thereby reducing neuroectoderm and neural crest induction and causing holoprosencephaly. Prenatal alcohol exposure (PAE) at premigratory stages elicits a different facial appearance, indicating FASD may represent a spectrum of facial outcomes. PAE at this premigratory period initiates a calcium transient that activates CaMKII and destabilizes transcriptionally active β-catenin, thereby initiating apoptosis within neural crest populations. Contributing to neural crest vulnerability are their low antioxidant responses. Ethanol-treated neural crest produce reactive oxygen species, and free radical scavengers attenuate their production and prevent apoptosis. Ethanol also significantly impairs neural crest migration, causing cytoskeletal rearrangements that destabilize focal adhesion formation; their directional migratory capacity is also lost. Genetic factors further modify vulnerability to ethanol-induced craniofacial dysmorphology, and include genes important for neural crest development including shh signaling, PDFGA, vangl2, and ribosomal biogenesis. Because facial and brain development are mechanistically and functionally linked, research into ethanol’s effects on neural crest also informs our understanding of ethanol’s CNS pathologies.

Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age

“…29,30 Furthermore, regarding the direct role of genes involved in alcohol metabolism in modifying risk, evidence from laboratory studies using ethanolsensitive and ethanol-resistant chickens, mice, and zebra fish provides insight into the multifactorial genetics of ethanol-mediated cell signaling disruption and neural crest apoptosis. 31 We observed that children of mothers who reported feeling the effects of alcohol quickly or very quickly exhibited larger craniofacial differences in most exposure groups. We hypothesize that this rate of feeling the effects of alcohol reflects genetically determined variation in alcohol metabolism.…”

“…31 Correlative face-brain phenotypes have been described in human and animal studies, suggesting that the type and severity of brain abnormality may be predicted in part by hypoplasia of the midface, 28,32 and that the classic facial features of FASD (short palpebral fissure, smooth philtrum, and thin upper lip) may assist in identifying children at risk of developing neurobehavioral deficits. 5 Given that cognitive outcomes for the children in our study have not yet been examined in this context, it is as yet unknown if the craniofacial differences found are of diagnostic or predictive value.…”

Transcriptome Profiling Identifies Ribosome Biogenesis as a Target of Alcohol Teratogenicity and Vulnerability during Early Embryogenesis

“…Previously we and others have reported that alcohol causes the apoptotic death of an early neuroprogenitor population called the neural crest [6–8]. Disruptions in neural crest development contribute to a characteristic craniofacial dysmorphology that can be diagnostic for some individuals who exhibit FASD morphological characteristics [9,10]. Using an established chick embryo model of alcohol exposure, we showed that alcohol causes craniofacial structural changes consistent with those of the human disorder [6,9].…”

Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis

“…[21][22][23]109,110 Studies linking animal models with human patients will be vital to advancing our understanding of FASD and to identify potential therapeutic approaches to overcome its catastrophic effects. Zebrafish is particularly well suited for studying the pathology of FASD because of its high fecundity, external fertilization, embryo transparency, rapid development time, and genetic tractability.…”