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Dev Biol 2015 Sep 01;4051:108-22. doi: 10.1016/j.ydbio.2015.07.001.
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The role of folate metabolism in orofacial development and clefting.

Wahl SE , Kennedy AE , Wyatt BH , Moore AD , Pridgen DE , Cherry AM , Mavila CB , Dickinson AJ .

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.

PubMed ID: 26144049
PMC ID: PMC4546841
Article link: Dev Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: casp3.2 dhfr grap2 h3-3a kit pcna rab40b rara slc19a1 tfap2a
Antibodies: Casp3 Ab1 FITC-phalloidin Lectin H3f3a Ab9 Methyl-H3f3a Ab18
Morpholinos: dhfr MO1

Disease Ontology terms: orofacial cleft
Phenotypes: Xla Wt + BMS453 (fig.7.b, c) [+]

Article Images: [+] show captions
References [+] :
Andersen, Incorporation of dUMP into DNA is a major source of spontaneous DNA damage, while excision of uracil is not required for cytotoxicity of fluoropyrimidines in mouse embryonic fibroblasts. 2005, Pubmed