The genetic background of thecurly tailstrain confers susceptibility to folate‐deficiency‐induced exencephaly

Abstract

BACKGROUND: Suboptimal maternal folate status is considered a risk factor for neural tube defects (NTDs). However, the relationship between dietary folate status and risk of NTDs appears complex, as experimentally induced folate deficiency is insufficient to cause NTDs in nonmutant mice. In contrast, folate deficiency can exacerbate the effect of an NTD-causing mutation, as in splotch mice. The purpose of the present study was to determine whether folate deficiency can induce NTDs in mice with a permissive genetic background which do not normally exhibit defects. METHODS: Folate deficiency was induced in curly tail and genetically matched wild-type mice, and we analyzed the effect on maternal folate status, embryonic growth and development, and frequency of NTDs. RESULTS: Folate-deficient diets resulted in reduced maternal blood folate, elevated homocysteine, and a diminished embryonic folate content. Folate deficiency had a deleterious effect on reproductive success, resulting in smaller litter sizes and an increased rate of resorption. Notably, folate deficiency caused a similar-sized, statistically significant increase in the frequency of cranial NTDs among both curly tail (Grhl3 mutant) embryos and background-matched embryos that are wild type for Grhl3. The latter do not exhibit NTDs under normal dietary conditions. Maternal supplementation with myo-inositol reduced the incidence of NTDs in the folate-deficient wild-type strain. CONCLUSIONS: Dietary folate deficiency can induce cranial NTDs in nonmutant mice with a permissive genetic background, a situation that likely parallels gene-nutrient interactions in human NTDs. Our findings suggest that inositol supplementation may ameliorate NTDs resulting from insufficient dietary folate. Birth Defects Research (Part A), 2010. © 2009 Wiley-Liss, Inc.

Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse

“…It is unclear whether the lack of protective effect of folic acid in the curly tail model reflects an underlying defect in FOCM. Nevertheless, curly tail embryos are sensitive to folate status, developing cranial neural tube defects at increased frequency under conditions of dietary folate deficiency (Burren et al , 2010). Moreover, in comparison with wild-types, curly tail embryos display abnormalities in levels of methylation cycle intermediates, including increased abundance of S -adenosylhomocysteine (de Castro et al , 2010).…”

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

“…A few studies suggest a beneficial effect of micronutrient supplementation on female fertility, but the available evidence is limited [Grajecki et al, 2012]. Another caveat is highlighted by the finding in the curly tail mouse model [Burren et al, 2010] that genetic background rather than the specific mutation at the Grhl3 locus confers predisposition to developmental defects under particular nutritional conditions. The chance for accumulation of such background polymorphisms is higher with mutant models—as compared to commercially available strains—since they are often bred in small colonies in individual laboratories where genetic drift may not be tightly controlled.…”

“… a High concentrations promote resorptions. b Supplementation also prolongs embryo survival. c Supplementation reduced branchial arch defects but not midline defects. d Folic acid reduces NTD incidence; high fat diet causes higher rate of cleft palate and heart defects but has no effect on NTDs. e Folate deficiency causes exencephaly in otherwise non-symptomatic mutants. f Increased resorptions and rate of neural tube defects, no effect on survival of particular genotypes. g Inositol supplementation significantly reduced survival of homozygotes and increased, among the survivors, the frequency of individuals with both exencephaly and spina bifida. h Significantly higher rate of resorptions, decreased survival of homozygous mutants, and a higher fraction of embryos had both exencephaly and spina bifida. i Reduced rate of exencephaly and spina bifida combined, greater incidence of exencephaly only. j Trend, reduction of neural tube defects was not significant. k Increased resorptions, decreased survival of homozygotes and decreased NTD incidence. l Short-term high folic acid promotes survival of homozygous mutants but has no effect on NTD incidence. m Long-term high folic acid detrimental to homozygote survival, and higher rate of NTDs. n Short-term high folic acid reduced NTD frequency; no effect on survival rates. o Long-term high folic acid reduced survival of homozygous mutants, but had no effect on NTD frequency. p Long-term high folic acid increased homozygote survival, and had marginal beneficial effect on NTD incidence. q Earlier lethality of homozygotes, higher rate of NTDs. r Appearance of NTDs in heterozygotes with short-term and long-term exposure to high folic acid; selective loss of homozygous mutants regardless of diet, and without effect on NTD incidence. s Non-significant trend toward higher incidence of NTD with long-term high folic acid diet. t Was reported before it was discovered that the genetic background alone (not Grhl3 genotype [Burren et al, 2010]) confers sensitivity to folate deficiency; responses to other nutrients were not specifically evaluated again. …”

“… t Was reported before it was discovered that the genetic background alone (not Grhl3 genotype [Burren et al, 2010]) confers sensitivity to folate deficiency; responses to other nutrients were not specifically evaluated again. …”

The emerging role of epigenetic mechanisms in the etiology of neural tube defects

“…82 Maternal folate deficiency also induces cranial NTDs in mouse embryos with a curly tail genetic background. 83 Again, a mechanism in which overall impairment of DNA methylation causes NTDs appears unlikely, since breeding the Mthfr null allele into the curly tail strain does not increase the frequency of defects despite major reduction in SAM/SAH ratio. 84 …”