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.

Role of JNK during buccopharyngeal membrane perforation, the last step of embryonic mouth formation

“…Longer exposure times often lead to severe effects where tissues separated from the face (n = 10; 1 experiment; not shown) and, therefore, were not assessed. We observed similar results when embryos were treated with chemicals shown to induce cell death in Xenopus (2% ethanol, Kot‐Leibovich and Fainsod, ; and methotrexate, Wahl et al, ; not shown). These results suggest that increased apoptosis is not the reason the buccopharyngeal membrane is failing to perforate in embryos deficient in JNK signals.…”

New Insights in Orofacial Cleft: Epidemiological and Genetic Studies on Italian Samples

“…Although some Authors did not find any evidence to confirm a positive association between the use of folic acid supplements during pregnancy and the risk of CP or CL±P (37), further evidence to support the role of folic acid was produced by other investigators (38,39). Methylenetetrahydrofolate reductase coded by MTHFR gene is a key enzyme in folic acid metabolism.…”

Modeling Human Craniofacial Disorders in Xenopus

“…To understand the role of folate metabolism in OFCs, the impact of folate reduction on Xenopus orofacial morphogenesis was examined alone, as well as in context of RA signaling. Using morpholino and pharmacological inhibitors targeting Dhfr, and face transplants the studies demonstrated that loss of folate metabolism can lead to alterations in the shape of the mouth and a narrower, underdeveloped face due to loss of jaw muscles and cartilages [51], a set of defects rescued by treatment with folinic acid.…”