Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Abstract

Summary Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith‐Magenis, Matthew‐Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

“…Interestingly, ethanol-sensitive signaling pathways detected during early embryogenesis were Wnt, Notch, and retinoic acid. Ethanol-induced dysregulation of retinoic acid signaling pathway was reported earlier 16,17,19,[38][39][40][41] . Our studies examining the heart and the eye in ethanol-treated embryos identified disruption of Wnt, Notch, retinoic acid and Bmp signaling pathways during organogenesis [17][18][19][20] .…”

What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

“…The variability of phenotype in this congenital disease is due to differences in the timing and amount of alcohol exposure during embryogenesis. Bird, rodent, frog, and zebrafish models of fetal alcohol syndrome utilize different exposure times and at various stages to understand the mechanisms underlying tissue damage (Joya, Garcia-Algar, Vall, & Pujades, 2014;Kiecker, 2016;Petrelli, Bendelac, Hicks, & Fainsod, 2019;Riley et al, 2011;Sulik, Johnson, & Webb, 1981;Sulik, Lauder, & Dehart, 1984;Zhang et al, 2014). The original hypothesis proposed that ethanol is a competitive inhibitor of the aldehyde dehydrogenase enzymes that are also important in the conversion of retinol to RA (Deltour et al, 1996;Duester, 1991).…”

Animal models of gene–alcohol interactions

“…Targets of RA signaling provide promising candidates for elucidating the mechanism by which RA may be involved in FASD. Top among these is Sonic Hedgehog (Shh) signaling (Petrelli, Bendelac, Hicks, & Fainsod, 2019). Loss of Shh pathway members results in holoprosencephaly (HPE) spectrum consisting of defects in neural tube development, loss of midline craniofacial structures, and neural crest-specific cell death (Chiang et al, 1996;Cordero et al, 2004;Eberhart et al, 2006;Jeong, Mao, Tenzen, Kottmann, & McMahon, 2004;Pan, Chatterjee, & Gerlai, 2012;Roessler & Muenke, 2010;Wada et al, 2005).…”