Gestational folate deficiency alters embryonic gene expression and cell function

Folic acid is a nutrient essential for embryonic development. Folate deficiency can cause embryonic lethality or neural tube defects and orofacial anomalies. Folate receptor 1 (Folr1) is a folate binding protein that facilitates the cellular uptake of dietary folate. To better understand the biological processes affected by folate deficiency, gene expression profiles of gestational day 9.5 (gd9.5) Folr1−/− embryos were compared to those of gd9.5 Folr1+/+ embryos. The expression of 837 genes/ESTs was found to be differentially altered in Folr1−/− embryos, relative to those observed in wild-type embryos. The 837 differentially expressed genes were subjected to Ingenuity Pathway Analysis. Among the major biological functions affected in Folr1−/− mice were those related to ‘digestive system development/function’, ‘cardiovascular system development/function’, ‘tissue development’, ‘cellular development’, and ‘cell growth and differentiation’, while the major canonical pathways affected were those associated with blood coagulation, embryonic stem cell transcription and cardiomyocyte differentiation (via BMP receptors). Cellular proliferation, apoptosis and migration were all significantly affected in the Folr1−/− embryos. Cranial neural crest cells (NCCs) and neural tube explants, grown under folate-deficient conditions, exhibited marked reduction in directed migration that can be attributed, in part, to an altered cytoskeleton caused by perturbations in F-actin formation and/or assembly. The present study revealed that several developmentally relevant biological processes were compromised in Folr1−/− embryos. [Display omitted] •Gene expression profiling was determined in Folate receptor 1 KO (Folr1−/−) embryos.•837 genes were differentially expressed in Folr1−/−, relative to Folr1+/+, embryos.•Increased apoptosis and decreased proliferation were noted in Folr1−/− cranial NCCs.•Directed migration of cranial NCCs was markedly affected in Folr1−/− embryos.•F-actin mediated cytoskeletal changes may impair NCC migration in Folr1−/− embryos.