Effects of excess vitamin A on development of cranial neural crest-derived structures: A neonatal and embryologic study

Genetic disruption of CYP26B1 severely affects development of neural crest derived head structures, but does not compromise hindbrain patterning

“…The lack of an abnormal hindbrain phenotype in Cyp26b1 Ϫ/Ϫ embryos, even at stages when Cyp26a1 and Cyp26c1 (E10 -E10.5) are no longer expressed indicates that at such stages either (i) the fate of hindbrain cells has already been specified and are thus resistant to further change due to the effects of RA or (ii) Raldh2 expression has retreated far enough posteriorly that RA is unable to diffuse into the hindbrain. We currently favor the latter explanation, as it has been demonstrated that administration of RA to pregnant mice at this stage of gestation can result in changes in hindbrain patterning, thus indicating that there is still plasticity in cell fate at this stage (Mulder et al, 2000).…”

“…RA has been identified as a teratogen and has the potential to affect many developing tissues, depending on the embryonic age at the time of exposure (Kochhar, 1973). Manifestations of RA teratogenicity include cleft palate, inner ear malformations, thymic agenesis, craniosynostosis, and hypoplasia of the mandible and maxilla (Yip et al, 1980;Mulder et al, 1998Mulder et al, , 2000Frenz and Liu, 2000;Collins et al, 2006). CNCCs contribute to the development of all of these structures, and it has been proposed that some of the teratogenic effects of RA may be due to abnormalities in NCC migration or differentiation (Uehara et al, 2007).…”

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

“…Interestingly, overexpression of Tbx1 can cause a similar spectrum of DGS-like defects to those observed in the haploinsufficiency models (Merscher et al, 2001). Previously, the effects of hyper-and hypovitaminosis A were attributed to defects within the neural crest, but a role in pharyngeal endodermal patterning now seems most likely (Lammer et al, 1985;Mulder et al, 1998Mulder et al, , 2000Wendling et al, 2000;Quinlan et al, 2002;Niederreither et al, 2003;Vermot et al, 2003), particularly because retinoic acid treatment of amphioxus embryos, which do not contain neural crest cells, results in loss of pharyngeal arches/pouches by means of action upon the pharyngeal endoderm (Escriva et al, 2002).…”

“…Human fetuses exposed to retinoids during gestation can phenocopy DGS (Happle et al, 1984;Lammer et al, 1985;Rosa et al, 1986). Exogenous retinoic acid applied to other vertebrate species, including monkeys and rodents results in similar anomalies (Kalter, 1960;Kalter and Warkany, 1961;Kochhar and Johnson, 1965;Shenefelt, 1972;Fantel et al, 1977;Kistler, 1981;Mulder et al, 1998Mulder et al, , 2000. Lack of retinoic acid is equally disruptive to the developing embryo; null mutations of the Raldh2 enzyme which generates the majority of embryonic RA, lead to mid-gestational lethality due to severe heart defects (Niederreither et al, 1999(Niederreither et al, , 2000(Niederreither et al, , 2001.…”

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

“…We present herein the incidence of overt early craniofacial phenotypes such as anterior truncations and open neural tube phenotypes using pellet (Sulik et al, 1995) 5 Pharyngeal arches (Taylor et al, 1995) 10 Palate (Wang et al, 2009), forelimb (Campbell et al, 2004), axial skeleton (Iulianella and Lohnes, 1997), Neural crest (Mallo and Brandlin, 1997;Mulder et al, 2000), heart (Wasiak and Lohnes, 1999), hindbrain (Morriss-Kay et al, 1991;Mahmood et al, 1996) 12 Hindbrain ((Morriss-Kay et al, 1991;Wood et al, 1994;Mahmood et al, 1996), pharyngeal arches (Mahmood et al, 1996) 3x 12.5 Neural tube closure/NTDs (Ehlers et al, 1992) 20 Limb (Kwasigroch et al, 1984), axial skeleton (Kawanishi et al, 2003), hindbrain (Conlon and Rossant, 1992;Marshall et al, 1992;Folberg et al, 1999), forebrain (Simeone et al, 1995) 25 Neural crest (Mulder et al, 2000), hindbrain (Leonard et al, 1995) 2x 25 Inner ear (Frenz et al, 1996;Frenz and Liu, 2000;Liu et al, 2008) 30 Palate, forelimb (Campbell et al, 2004), axial skeleton (Kawanishi et al, 2003), midbrain, forebrain (Simeone et al, 1995;Avantaggiato et al, 1996;Zhang et al, 2003) 40 Limb (Kwasigroch et al, 1984), axial skeleton (Kawanishi et al, 2003) 50 Neural crest (Mulder et al, 2000), inner ear (Frenz et al, 1996) 60 Palate, forelimb …”