title: Animal models for human craniofacial malformations.
abstract: Holoprosencephaly malformations, of which the fetal alcohol syndrome appears to be a mild form, can result from medial anterior neural plate deficiencies as demonstrated in an ethanol treated animal model. These malformations are associated with more medial positioning of the nasal placodes and resulting underdevelopment or absence of the medial nasal prominences (MNPs) and their derivatives. Malformations seen in the human retinoic acid syndrome (RAS) can be produced by administration of the drug 13-cis-retinoic acid in animals. Primary effects on neural crest cells account for most of these RAS malformations. Many of the malformations seen in the RAS are similar to those of hemifacial microsomia, suggesting similar neural crest involvement. Excessive cell death, apparently limited to trigeminal ganglion neuroblasts of placodal origin, follows 13-cis retinoic acid administration at the time of ganglion formation and leads to malformations virtually identical to those of the Treacher Collins syndrome (TCS). Secondary effects on neural crest cells in the area of the ganglion appear to be responsible for the TCS malformations. Malformations of the DiGeorge Syndrome are similar to those of the RAS and can be produced in mice by ethanol administration or by "knocking out" a homeobox gene (box 1.5). Human and animal studies indicate that cleft lips of multifactorial etiology may be generically susceptible because of small MNP)s or other MNP developmental alterations, such as those found in A/J mice, that make prominence contact more difficult. Experimental maternal hypoxia in mice indicates that cigarette smoking may increase the incidence of cleft lip by interfering with morphogenetic movements. Other human cleft lips may result from the action of a single major gene coding for TGF-alpha variants. A study with mouse palatal shelves in culture and other information suggest that a fusion problem may be involved.
authors.affiliation: Dental Research Center, School of Dentistry, University of North Carolina, Chapel Hill 27599.
authors.forename: M C
authors.initials: MC
authors.lastname: Johnston
authors.forename: P T
authors.initials: PT
authors.lastname: Bronsky
mesh_terms: D000818:Animals; D002971:Cleft Lip / Q000209:etiology; D002972:Cleft Palate / Q000209:etiology; D004062:DiGeorge Syndrome / Q000209:etiology; D004195:Disease Models, Animal; D004475:Ectoderm / Q000502:physiology; D005145:Face / Q000196:embryology*; D005146:Facial Asymmetry / Q000209:etiology; D005147:Facial Bones / Q000002:abnormalities*; D016142:Holoprosencephaly / Q000209:etiology; D006801:Humans; D015474:Isotretinoin / Q000009:adverse effects; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009672:Notochord / Q000502:physiology; D012886:Skull / Q000002:abnormalities* / Q000196:embryology*
chemical_list: D015474:Isotretinoin