Fetal Alcohol Spectrum Disorder as a Retinoic Acid Deficiency Syndrome

Fainsod, Abraham; Abbou, Tali; Bendelac-Kapon, Liat; Edri, Tamir; Pillemer, Graciela

doi:10.1007/978-1-0716-2613-9_4

Cited by 2 publications

(3 citation statements)

References 198 publications

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“…Our previous studies showed that EtOH exposure induces developmental malformations recapitulating the FAS phenotype by inhibiting RA biosynthesis and reducing RA signaling ( Shabtai et al, 2018 ; Fainsod et al, 2022 ). Therefore, we also employed EtOH as an additional inhibitor of RA production to further corroborate the involvement of RA signaling in the NTC process and the induction of closure defects.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Based on the biochemical similarity between alcohol clearance and RA biosynthesis and the possible overlapping use of enzymes during embryogenesis, the enzymatic competition between both processes has been studied (reviewed in Shabtai and Fainsod, 2018 ; Fainsod et al, 2022 ). Multiple developmental malformations characteristic of FAS, such as craniofacial abnormalities, fetal growth restriction, microcephaly, and EtOH-induced abnormal morphogenetic movements, and gene expression changes, were recapitulated by reducing RA signaling levels (reviewed in Fainsod et al, 2022 ). In agreement, RA has been shown to rescue the teratogenic effects of alcohol exposure in vertebrate embryos ( Graham and Ferm, 1985 ; Wang et al, 2009 ; Serrano et al, 2010 ; Ballard et al, 2012 ; Hwang et al, 2012 ; Sarmah and Marrs, 2013 ; Muralidharan et al, 2015 ; Gupta et al, 2016 ; Ojeda et al, 2018 ; Rah et al, 2018 ; Cadena et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

Edri,

Cohen,

Shabtai

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Neural tube defects (NTDs) are among the most debilitating and common developmental defects in humans. The induction of NTDs has been attributed to abnormal folic acid (vitamin B9) metabolism, Wnt and BMP signaling, excess retinoic acid (RA), dietary components, environmental factors, and many others. In the present study we show that reduced RA signaling, including alcohol exposure, induces NTDs.Methods:Xenopus embryos were exposed to pharmacological RA biosynthesis inhibitors to study the induction of NTDs. Embryos were treated with DEAB, citral, or ethanol, all of which inhibit the biosynthesis of RA, or injected to overexpress Cyp26a1 to reduce RA. NTD induction was studied using neural plate and notochord markers together with morphological analysis. Expression of the neuroectodermal regulatory network and cell proliferation were analyzed to understand the morphological malformations of the neural plate.Results: Reducing RA signaling levels using retinaldehyde dehydrogenase inhibitors (ethanol, DEAB, and citral) or Cyp26a1-driven degradation efficiently induce NTDs. These NTDs can be rescued by providing precursors of RA. We mapped this RA requirement to early gastrula stages during the induction of neural plate precursors. This reduced RA signaling results in abnormal expression of neural network genes, including the neural plate stem cell maintenance genes, geminin, and foxd4l1.1. This abnormal expression of neural network genes results in increased proliferation of neural precursors giving rise to an expanded neural plate.Conclusion: We show that RA signaling is required for neural tube closure during embryogenesis. RA signaling plays a very early role in the regulation of proliferation and differentiation of the neural plate soon after the induction of neural progenitors during gastrulation. RA signaling disruption leads to the induction of NTDs through the mis regulation of the early neuroectodermal network, leading to increased proliferation resulting in the expansion of the neural plate. Ethanol exposure induces NTDs through this mechanism involving reduced RA levels.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

Edri,

Cohen,

Shabtai

et al. 2023

Front. Cell Dev. Biol.

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Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly

Gur

Bendelac-Kapon

Shabtai

et al. 2022

Front. Cell Dev. Biol.

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Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation in Xenopus embryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.

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Fetal Alcohol Spectrum Disorder as a Retinoic Acid Deficiency Syndrome

Cited by 2 publications

References 198 publications

Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly

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