Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development

Abstract

Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly. Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans.

Spatial and temporal expression of folate‐binding protein 1 (Fbp1) is closely associated with anterior neural tube closure in mice

“…This assumption is consistent with the previous report that the first branchial arch and trigeminal ganglia suffer severe growth defects in Fbp1(-/-) embryos (Piedrahita et al, 1999). Because the neural crest cells derived from r2 are major components of the first branchial arch and trigeminal ganglia, growth defects of these structures in Fbp1(-/-) embryos indicate that Fbp1 is required for proliferation of r2-derived neural crest cells.…”

“…Mouse embryos lacking Fbp1 show severe morphologic abnormalities in the prosencephalon, mesencephalon, optic vesicle, otic placode, and branchial arches (Piedrahita et al, 1999). None of Fbp1(-/-) embryos complete neural tube closure and survive beyond embryonic day 10 (E10), whereas Fbp2(-/-) mutants develop into apparently healthy adults.…”

“…None of Fbp1(-/-) embryos complete neural tube closure and survive beyond embryonic day 10 (E10), whereas Fbp2(-/-) mutants develop into apparently healthy adults. Chronic suprapharmacologic doses of folate (25 mg/kg) can rescue the Fbp1(-/-) phenotypes (Piedrahita et al, 1999;Rosenquist and Finnell, 2001), probably due to passive diffusion of folate into cells. Furthermore, an antisense oligonucleotide against FBP1 mRNA causes NTD in a dose-dependent manner when injected into the amniotic sac of mouse embryos (Antony and Hansen, 2000).…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…Knockout mouse pathogenesis CBS [137][138][139][140] Hyperhomocysteinemia Hyperkeratosis MAT1A 89 Spontaneous hepatocellular carcinoma and impaired liver regeneration MTHFR 85,141 Hyperhomocysteinemia (À/+ and À/À) Developmental retardation with cerebellar pathology (À/À) Aortic lipid deposition (À/+ and À/À) Abnormal spermatogenesis (À/À) FOLR1 (Folbp1 Embryonic lethality (À/À) mouse homolog) 90 reversed by folinic acid supplementation of (À/+) dams…”

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

“…Results from another of the laboratories collaborating in this study showed multiple developmental abnormalities related to the massive die-off of neural tube and neural crest cells in Folbp1À/À (Folr1À/À) knockout mouse (Piedrahita et al, 1999;Zhu et al, 2007), damage that was far more extensive than is the case for the current study. These contrasting results demonstrate a difference between the global loss of Folbp1 and its reduced expression in a highly focused spatiotemporal manner.…”