Embryonic development of folate binding protein‐1 (Folbp1) knockout mice: Effects of the chemical form, dose, and timing of maternal folate supplementation

Abstract

Inactivation of folate binding protein-1 (Folbp1) adversely impacts murine embryonic development, as nullizygous embryos (Folbp1 -/-) die in utero. Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects. We examined whether maternal supplementation with L-N5-methyl-tetrahydrofolate (L-5M-THF) has superior protective effects on embryonic development of Folbp1 -/-fetuses compared with L-N5-formyl-tetrahydrofolate (L-5F-THF). We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1 -/-embryos. Folbp1 -/-pups presented with a range of malformations involving the neural tube, craniofacies, eyes, and abdominal wall. The frequencies of these malformations decreased with increasing folate dose, regardless of the form used. There was no additional benefit provided by L-5M-THF compared with L-5F-THF. Despite rescuing the phenotype in Folbp1 -/-embryos, no significant elevation of Folbp1 -/-maternal folate levels was observed with supplementation.

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

“…3A). These results identify Folr1 as a relevant molecule in the process of Xenopus neurulation, in agreement with what has been reported in other model systems (Spiegelstein et al, 2004), and suggest that the interaction between folate and its receptor is necessary for neural tube formation. We ruled out the (G) Graph shows area labeled by apical Folr1 immunostaining in three wild-type and morpholino-containing medial neural plate cells (indicated with brackets in E,F).…”

“…In mice, knockout of Folr1 results in an open neural tube by embryonic day 9.5, when heterozygotes or wild-type littermate embryos show a closed neural tube. This phenotype leads to death of homozygous embryos in utero (Finnell et al, 2002;Piedrahita et al, 1999;Spiegelstein et al, 2004;Wallingford et al, 2013). The specific cellular mechanisms dependent on Folr1 during mouse neural tube formation are unclear.…”

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

“…More than 10 folate-related mouse mutants have been characterized thus far (16), but NTDs are observed in only three: Folr1, Shmt1, and Amt. Folr1 encodes folate receptor 1, one of the major folate transport systems, and homozygous knockout of Folr1 produces a severe folate deficiency in the embryo that can be rescued with maternal 5-formyl-THF supplementation (17). This rescue is "tunable," and depending on the dose of 5-formyl-THF administered to mothers during gestation, Folr1 −/− embryos develop NTDs and orofacial deformities or can be rescued to birth.…”

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida

“…The Folr1 (folate binding protein 1) knockout mouse is a well-established animal model for folate-responsive NTDs. Mice lacking Folr1 gene die prematurely in utero around gestational day 10 (E10) [4,5]. The null embryos can be partially rescued by supplementing the pregnant dams with 25 mg/kg/day S-folinic acid, although a reduced number of nullizygous pups will still present with exencephaly [5].…”

“…Mice lacking Folr1 gene die prematurely in utero around gestational day 10 (E10) [4,5]. The null embryos can be partially rescued by supplementing the pregnant dams with 25 mg/kg/day S-folinic acid, although a reduced number of nullizygous pups will still present with exencephaly [5]. A recent microarray study using this mouse model provided intriguing evidence that Pcmt1, the gene encoding methyl-transferase, L-isoaspartate (D-aspartate) Omethyltransferase (PIMT, E.C.…”