Folate-Regulated Changes in Gene Expression in the Anterior Neural Tube of Folate Binding Protein-1 (Folbp1)-Deficient Murine Embryos

Abstract

Inactivation of the murine folate binding protein-1 (Folbp1) has been shown to play a vital role in embryonic development. Nullizygous embryos (Folbp1-/-) have significant malformations of the neural tube, craniofacies, and conotruncus, and invariably die in utero by gestational day (E) 10. Administration of 25 mg x kg(-1) x day(-1) folinic acid to dams prior to and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develops neural tube defects. Using antisense RNA amplification and cDNA microarrays, we examined the expression of approximately 5700 genes in the anterior neural tube of gestational day 9 Folbp1-/- embryos that were supplemented with folinic acid. Genes that appear to be folate regulated include transcription factors, G-proteins, growth factors, methyltransferases, and those that are related to cell proliferation. The potential impact of such changes during neural tube closure is considered in light of the phenotype of Folbp1-/- embryos.

Neural tube defects and folate: case far from closed

“…This small study suggests that maternal autoantibodies that bind to the folate receptor, and so block the intracellular uptake of folate by target epithelial cells, might cause NTDs, which could explain the beneficial effect of periconceptional folate supplementation. In support of this, the lack of folate available to the developing embryo secondary to a defective or blocked folate receptor has been shown to increase the risk of folate-responsive congenital anomalies in experimental animal model systems [23][24][25][26][27] .…”

“…This small study suggests that maternal autoantibodies that bind to the folate receptor, and so block the intracellular uptake of folate by target epithelial cells, might cause NTDs, which could explain the beneficial effect of periconceptional folate supplementation. In support of this, the lack of folate available to the developing embryo secondary to a defective or blocked folate receptor has been shown to increase the risk of folate-responsive congenital anomalies in experimental animal model systems [23][24][25][26][27] .Another body of evidence that suggests that altered folate metabolism contributes to abnormal neural tube development derives from analyses of postpartum serum. Several clinical studies indicate that folate concentrations in postpartum serum and red blood cells are lower among women who have previously had a child with an NTD 28-30 ; however, there have been conflicting results, with some studies failing to find such an association [31][32][33][34][35] .…”

Novel functions of folate receptor alpha in CNS development and diseases

“…The role of FRα in neural tube defects has been very well documented [12]. Inactivation of the murine folate binding protein-1 (Folbp1) in nullizygous embryos (Folbp1-/-) show significant malformations of the neural tube, craniofacial abnormalities, and conotruncus, and invariably die in utero by gestational day (E10) [13].…”

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

“…They accumulate Lisoaspartyl residues in several tissues and die, on average, 42 days after birth from progressive epileptic seizures (Kim et al 1997). The Pcmt1 gene was upregulated in Folr1 (folate-binding protein 1) nullizygous mouse neural tube tissues when the normal phenotype was rescued with folic acid supplementation (Spiegelstein et al 2004). Therefore, PIMT might act to trigger the repair of isoaspartate protein damage, and this damage might increase if Hcy or SAH levels are elevated or folate levels are reduced.…”