title: The role of folate metabolism in orofacial development and clefting.
abstract: Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects.
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Stacey E
authors.initials: SE
authors.lastname: Wahl
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Allyson E
authors.initials: AE
authors.lastname: Kennedy
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Brent H
authors.initials: BH
authors.lastname: Wyatt
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Moore
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Pridgen
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Cherry
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Mavila
authors.affiliation: Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States. Electronic address: ajdickinson@vcu.edu.
authors.forename: Amanda J G
authors.initials: AJ
authors.lastname: Dickinson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002972:Cleft Palate / Q000196:embryology* / Q000378:metabolism*; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D005145:Face / Q000196:embryology*; D005492:Folic Acid / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D008954:Models, Biological; D060172:Morpholinos / Q000494:pharmacology; D009055:Mouth / Q000196:embryology* / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D009432:Neural Crest / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D015415:Biomarkers; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D002955:Leucovorin; D008727:Methotrexate
keywords: DHFR; Folate; Orofacial development; Retinoic acid and primary palate; Xenopus