8 Fetal Alcohol Spectrum Disorder: Embryogenesis Under …
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produce developmental malformations that resemble those induced by excess ethanol
exposure during pregnancy (Hollemann et al. 1998; de Roos et al. 1999; Yelin et al.
2007). Reducing RA levels in the developing fetus by infusing RA biosynthesis
inhibitors, such as DEAB (Russo et al. 1988) or citral, into the pregnant mother also
induces developmental malformations that show overlap with the defects observed in
ethanol treated embryos and individuals with FAS (Kikonyogo et al. 1999; Anchan
et al. 1997). A number of studies have taken advantage of other approaches (v-erbA
overexpression, anti-RA monoclonal antibodies, overexpression of mutant retinoid
receptors, pharmacological rescue) to inhibit and study the role of RA during embryogenesis (Perz-Edwards et al. 2001; Chawla et al. 2018; Le et al. 2012; Schuh et al.
1993; Di Renzo et al. 2007; Sharpe and Goldstone 2000; Twal and Zile 1997; Janesick
et al. 2014). Also in this case, many of the developmental defects observed from RA
signaling knockdown overlap with malformations normally described in individuals
with FASD or embryonic experimental models exposed with ethanol.
Mutations or knockdown of RA metabolic or signaling genes also produce a
reduction of RA levels. Mutation of the aldh1A2 gene results in early embryonic
lethality (Niederreither et al. 1999; Begemann et al. 2001). Before they die, the
aldh1A2 mutant embryos exhibit malformations in forebrain and optic and otic vesicle development that are reminiscent of malformations observed in FAS (Mic et al.
2004; Ribes et al. 2006; Molotkova et al. 2007). RALDH3, RDH10 and RDHe2
enzymes perform essential RA biosynthetic activities in vertebrate gastrula embryos
in parallel to those performed by RALDH2. Mutation of aldh1A3 (Dupé et al. 2003;
Molotkova et al. 2007), rdh10 (Sandell et al. 2007; Rhinn et al. 2011), and rar genes
result in developmental malformations, including forebrain and head malformations,
that partially overlap with the FAS phenotype (Lohnes et al. 1994; Mendelsohn et al.
1994; Mark et al. 2009). Moreover, RDHe2 and RDH10 knockdown in Xenopus
embryos results in microcephaly, a malformation common in individuals with FAS
(Belyaeva et al. 2012; Strate et al. 2009; Popova et al. 2016).
Matthew-Wood Syndrome is induced by mutations in the stra6 (stimulated by
retinoic acid 6) gene, which encodes a receptor for vitamin A. Smith-Magenis Syndrome has been characterized as an haploinsufficiency of the RAI1 (retinoic acid
induced 1) gene. DiGeorge syndrome—a sporadic autosomal dominant disorder—is
actually caused by a micro-hemizygous deletion on chromosome 22 encompassing
approximately 30 genes (22q11) (Scambler et al. 1991; Driscoll et al. 1993). One
of the genes included in the deletion is tbx1, a transcription factor encoding gene.
Heterozygous tbx1 mutant mice phenocopy many the malformations observed in
DiGeorge Syndrome patients (Baldini 2005). TBX1 is known to promote the expression of the cyp26 gene family (Roberts et al. 2006). These details would suggest
that overexpression of RA phenocopies DiGeorge Syndrome but this is only a partial explanation. Interestingly, RA deficiency in a vitamin A deficient quail model
or in mice mutant for aldh1A2 also showed disruption of tbx1 expression (Vermot
et al. 2003; Roberts et al. 2005). Recently, ripply3 (also known as Down syndrome
critical region 6, dscr6), a co-repressor of tbx1 was shown to be regulated by RA
(Okubo et al. 2011; Janesick et al. 2012; Okubo 2014). Therefore, tbx1 regulation
and function might be regulated by RA through its co-repressor.
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produce developmental malformations that resemble those induced by excess ethanol
exposure during pregnancy (Hollemann et al. 1998; de Roos et al. 1999; Yelin et al.
2007). Reducing RA levels in the developing fetus by infusing RA biosynthesis
inhibitors, such as DEAB (Russo et al. 1988) or citral, into the pregnant mother also
induces developmental malformations that show overlap with the defects observed in
ethanol treated embryos and individuals with FAS (Kikonyogo et al. 1999; Anchan
et al. 1997). A number of studies have taken advantage of other approaches (v-erbA
overexpression, anti-RA monoclonal antibodies, overexpression of mutant retinoid
receptors, pharmacological rescue) to inhibit and study the role of RA during embryogenesis (Perz-Edwards et al. 2001; Chawla et al. 2018; Le et al. 2012; Schuh et al.
1993; Di Renzo et al. 2007; Sharpe and Goldstone 2000; Twal and Zile 1997; Janesick
et al. 2014). Also in this case, many of the developmental defects observed from RA
signaling knockdown overlap with malformations normally described in individuals
with FASD or embryonic experimental models exposed with ethanol.
Mutations or knockdown of RA metabolic or signaling genes also produce a
reduction of RA levels. Mutation of the aldh1A2 gene results in early embryonic
lethality (Niederreither et al. 1999; Begemann et al. 2001). Before they die, the
aldh1A2 mutant embryos exhibit malformations in forebrain and optic and otic vesicle development that are reminiscent of malformations observed in FAS (Mic et al.
2004; Ribes et al. 2006; Molotkova et al. 2007). RALDH3, RDH10 and RDHe2
enzymes perform essential RA biosynthetic activities in vertebrate gastrula embryos
in parallel to those performed by RALDH2. Mutation of aldh1A3 (Dupé et al. 2003;
Molotkova et al. 2007), rdh10 (Sandell et al. 2007; Rhinn et al. 2011), and rar genes
result in developmental malformations, including forebrain and head malformations,
that partially overlap with the FAS phenotype (Lohnes et al. 1994; Mendelsohn et al.
1994; Mark et al. 2009). Moreover, RDHe2 and RDH10 knockdown in Xenopus
embryos results in microcephaly, a malformation common in individuals with FAS
(Belyaeva et al. 2012; Strate et al. 2009; Popova et al. 2016).
Matthew-Wood Syndrome is induced by mutations in the stra6 (stimulated by
retinoic acid 6) gene, which encodes a receptor for vitamin A. Smith-Magenis Syndrome has been characterized as an haploinsufficiency of the RAI1 (retinoic acid
induced 1) gene. DiGeorge syndrome—a sporadic autosomal dominant disorder—is
actually caused by a micro-hemizygous deletion on chromosome 22 encompassing
approximately 30 genes (22q11) (Scambler et al. 1991; Driscoll et al. 1993). One
of the genes included in the deletion is tbx1, a transcription factor encoding gene.
Heterozygous tbx1 mutant mice phenocopy many the malformations observed in
DiGeorge Syndrome patients (Baldini 2005). TBX1 is known to promote the expression of the cyp26 gene family (Roberts et al. 2006). These details would suggest
that overexpression of RA phenocopies DiGeorge Syndrome but this is only a partial explanation. Interestingly, RA deficiency in a vitamin A deficient quail model
or in mice mutant for aldh1A2 also showed disruption of tbx1 expression (Vermot
et al. 2003; Roberts et al. 2005). Recently, ripply3 (also known as Down syndrome
critical region 6, dscr6), a co-repressor of tbx1 was shown to be regulated by RA
(Okubo et al. 2011; Janesick et al. 2012; Okubo 2014). Therefore, tbx1 regulation
and function might be regulated by RA through its co-repressor.