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Crooked tail (Cd) models human folate-responsive neural tube defects
1Laboratory of Molecular Neurobiology and Development, Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA.
Abstract:
Genetic correlation of human neural tube defects (NTDs) with NTD genes identified in mouse may unravel predisposing complex traits for assessment of individual risk and treatment in clinical settings. Folic acid (FA) can reduce the recurrence of NTDs in human populations by as much as 50-70%, though the mechanism of this rescue is unknown. We examined whether Crooked tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs. The Cd locus was localized to a 0.2 cM interval of the Mouse Genome Database genetic map, identifying tightly linked markers for genotyping prior to phenotypic expression. In a controlled diet study, Cd was found to mimic closely the clinical response to FA. FA supplementation reduced the recurrence risk of Cd exencephaly by as much as 55%. This rescue was dose dependent and did not require subjects to be inherently folate deficient. Like the female predominance of NTDs in humans, female Cd embryos were most likely to display exencephaly and were more responsive than males to the FA rescue. Importantly, FA supplementation shifted the severity of Cd phenotypic expression from early embryonic lethality to longer survival, and reduced the incidence of NTDs. The Cd locus is distinct from the known genes associated with neurulation defects, and isolation of this gene will assist identification of biochemical, genetic and gender-dependent factors contributing to folate-responsive NTDs.
Insights
A mouse model for neural tube defects (NTDs) shows folic acid (FA) significantly reduces NTD recurrence. This genetic model mimics human responses, aiding risk assessment and treatment strategies for folate-responsive NTDs.
Area of Science:
- Developmental biology
- Genetics
- Neuroscience
Background:
- Neural tube defects (NTDs) are common birth defects with complex genetic origins.
- Folic acid (FA) supplementation reduces NTD recurrence in humans, but the mechanism remains unclear.
- Identifying genetic models is crucial for understanding NTD pathogenesis and folate's role.
Purpose of the Study:
- To investigate the mouse strain Crooked tail (Cd) as a genetic model for folate-responsive NTDs.
- To elucidate the mechanism of folic acid's protective effect against NTDs.
- To identify genetic and gender-dependent factors contributing to NTDs.
Main Methods:
- Localization of the Cd locus using genetic mapping.
- Controlled diet studies assessing the effect of folic acid supplementation on Cd exencephaly.
- Comparative analysis of phenotypic expression and response to FA between male and female Cd embryos.
Main Results:
- The Cd locus was mapped to a specific genetic interval.
- Folic acid supplementation reduced exencephaly recurrence in Cd mice by 55% in a dose-dependent manner.
- Female Cd embryos exhibited higher susceptibility and greater response to FA rescue, mirroring human NTD patterns.
Conclusions:
- The Cd mouse strain serves as a valuable genetic model for studying folate-responsive NTDs.
- Folic acid's protective effect is independent of folate deficiency and influences NTD severity and survival.
- Further characterization of the Cd gene will reveal key factors in NTD development and gender-specific responses.