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Mouse models of neural tube defects: investigating preventive mechanisms
Nicholas D E Greene1, Andrew J Copp
1Neural Development Unit, Institute of Child Health, University College London, UK. n.greene@ich.ucl.ac.uk
Abstract:
Neural tube defects (NTD), including anencephaly and spina bifida, are a group of severe congenital abnormalities in which the future brain and/or spinal cord fail to close. In mice, NTD may result from genetic mutations or knockouts, or from exposure to teratogenic agents, several of which are known risk factors in humans. Among the many mouse NTD models that have been identified to date, a number have been tested for possible primary prevention of NTD by exogenous agents, such as folic acid. In genetic NTD models such as Cart1, splotch, Cited2, and crooked tail, and NTD induced by teratogens including valproic acid and fumonisins, the incidence of defects is reduced by maternal folic acid supplementation. These folate-responsive models provide an opportunity to investigate the possible mechanisms underlying prevention of NTD by folic acid in humans. In another group of mouse models, that includes curly tail, axial defects, and the Ephrin-A5 knockout, NTD are not preventable by folic acid, reflecting the situation in humans in which a subset of NTD appear resistant to folic acid therapy. In this group of mutants alternative preventive agents, including inositol and methionine, have been shown to be effective. Overall, the data from mouse models suggests that a broad-based in utero therapy may offer scope for prevention of a greater proportion of NTD than is currently possible.
Insights
Mouse models reveal that folic acid prevents some neural tube defects (NTD), while others require alternative therapies like inositol or methionine for prevention.
Area of Science:
- Developmental Biology
- Teratology
- Genetics
Background:
- Neural tube defects (NTD) are severe congenital abnormalities affecting brain and spinal cord development.
- Mouse models, induced by genetic factors or teratogens, mimic human NTD and are crucial for research.
- Folic acid is a known preventive agent for some NTDs, but resistance exists.
Purpose of the Study:
- To investigate the efficacy of folic acid and alternative agents in preventing various mouse NTD models.
- To understand the mechanisms of folate-responsive and folate-resistant NTDs.
- To explore broader therapeutic strategies for NTD prevention.
Main Methods:
- Utilized genetic and teratogen-induced mouse models of NTD.
- Administered folic acid supplementation to pregnant dams.
- Tested alternative preventive agents such as inositol and methionine in folate-resistant models.
Main Results:
- Maternal folic acid supplementation reduced NTD incidence in folate-responsive models (e.g., Cart1, splotch, valproic acid-induced).
- NTD in folate-resistant models (e.g., curly tail, Ephrin-A5 knockout) were not prevented by folic acid.
- Inositol and methionine effectively prevented NTD in specific folate-resistant mouse models.
Conclusions:
- Mouse models demonstrate differential responses to folic acid for NTD prevention.
- Folate-resistant NTDs may be preventable with alternative in utero therapies.
- A comprehensive approach using various agents could enhance overall NTD prevention rates.
