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Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

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Examples of congenital defects inApobandLpmutant mice. A. Normal embryo, B. Apob – exencephaly, C. Lp – craniorachischosis, and D. Lp – loop-tail.
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Figure 1: Examples of congenital defects inApobandLpmutant mice. A. Normal embryo, B. Apob – exencephaly, C. Lp – craniorachischosis, and D. Lp – loop-tail.

Mentions: We examined the FA response of two NTD mouse mutants. Apolipoprotein B (apoB) is a key structural component of several lipoproteins that transport circulating cholesterol, lipids, and vitamin E [27]. The Apobtm1Unc mutant is the result of a genetically engineered loss-of-function (LOF) mutation in the Apob gene [27]. Apob homozygous embryos show a 30% penetrance of exencephaly alone or accompanied with hydrocephalus [27], see also [28] (Figure 1A vs B). By 8 weeks of age, mutants that have a closed neural tube show hydrocephalus in 32% of homozygotes and in 1% of heterozygotes. VANGL2 protein is one of two highly conserved membrane proteins involved in establishing planar cell polarity (PCP) and in regulating convergent extension movements during embryogenesis [29]. The Vangl2Lp mutant results from a spontaneous LOF mutation in the Vangl2 gene [29], see also [28]. Lp homozygous embryos have a 100% penetrance of craniorachischisis due to failure to initiate neural tube closure at embryonic day E8.5 [30] (Figure 1A vs C). This mutation is inherited in a co-dominant manner and the heterozygous phenotype is characterized by a looped tail resulting from vertebral anomalies [29] (Figure 1A vs D). Neither mutant has been previously tested for response to dietary FA supplementation.


Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Examples of congenital defects inApobandLpmutant mice. A. Normal embryo, B. Apob – exencephaly, C. Lp – craniorachischosis, and D. Lp – loop-tail.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4151023&req=5

Figure 1: Examples of congenital defects inApobandLpmutant mice. A. Normal embryo, B. Apob – exencephaly, C. Lp – craniorachischosis, and D. Lp – loop-tail.
Mentions: We examined the FA response of two NTD mouse mutants. Apolipoprotein B (apoB) is a key structural component of several lipoproteins that transport circulating cholesterol, lipids, and vitamin E [27]. The Apobtm1Unc mutant is the result of a genetically engineered loss-of-function (LOF) mutation in the Apob gene [27]. Apob homozygous embryos show a 30% penetrance of exencephaly alone or accompanied with hydrocephalus [27], see also [28] (Figure 1A vs B). By 8 weeks of age, mutants that have a closed neural tube show hydrocephalus in 32% of homozygotes and in 1% of heterozygotes. VANGL2 protein is one of two highly conserved membrane proteins involved in establishing planar cell polarity (PCP) and in regulating convergent extension movements during embryogenesis [29]. The Vangl2Lp mutant results from a spontaneous LOF mutation in the Vangl2 gene [29], see also [28]. Lp homozygous embryos have a 100% penetrance of craniorachischisis due to failure to initiate neural tube closure at embryonic day E8.5 [30] (Figure 1A vs C). This mutation is inherited in a co-dominant manner and the heterozygous phenotype is characterized by a looped tail resulting from vertebral anomalies [29] (Figure 1A vs D). Neither mutant has been previously tested for response to dietary FA supplementation.

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

Show MeSH
Related in: MedlinePlus