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case1246538783.pdf (1.47 MB)
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Genetic and Phenotypic Response of Neural Tube Defect Mouse Mutants to Folic Acid
Author Info
Nakouzi, Ghunwa Akram
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1246538783
Abstract Details
Year and Degree
2009, Doctor of Philosophy, Case Western Reserve University, Genetics.
Abstract
Supplementation with folic acid (FA) is a public health policy to reduce the risk of neural tube defects (NTDs). However, compliance with recommended levels is low, and ≈50% of women and their babies are resistant to the beneficial effect of FA. If NTD response to FA could be predicted, compliance might improve and treatment could be targeted directly to responsive women. To test for maternal markers of fetal NTD risk and FA response, mouse models were used. Females of six single gene mouse mutants that are prone to NTD affected pregnancies were studied, among which three had an untested response to FA. We found that the NTD phenotype of these three mutants was resistant to maternal FA supplementation. Unexpectedly, these three mutants showed a substantial FA-induced loss of homozygous and heterozygous pre-implantation embryos. With two responsive and four resistant NTD mutants, whole genome expression and metabolite profiles were then analyzed to identify maternal markers for occurrence of fetal NTDs and FA response. Canonical pathways related to retinoid X receptor (RXR) function were associated with all NTD mutants regardless of FA response. By contrast, no specific pathways distinguished NTD-responsive and -resistant mutants, suggesting that multiple mechanisms control response to FA. Finally, gene expression analysis verified with
in vitro
assays showed that FA supplementation affected both Wnt/β-catenin signaling and cell cycle regulation in the
Lrp6
mutant. Overall, FA-induced loss of homozygous as well as otherwise healthy and viable heterozygous embryos highlight the need to determine the cause and stage of this early embryonic lethality. Moreover, the association of RXR related pathways with all six NTD mutants suggests a shared mechanism for NTD pathogenesis in which the role of RXR should be investigated. Our studies of the
Lrp6
loss-of-function mutant, together with published work of the
Lrp6
gain-of-function mutant, suggest that FA supplementation attenuates canonical Wnt signaling to normal levels in the latter mutant thereby restoring normal neural tube development, and to sub-optimal levels in the former mutant thereby compromising embryonic viability. The mechanisms by which FA affects Wnt signaling and the functional dependence of neural tube development on the level of Wnt signaling remain to be determined.
Committee
Joseph Nadeau (Advisor)
Shawn McCandless (Committee Chair)
Mark Adams (Committee Member)
Radhika Atit (Committee Member)
Donald Jacobsen (Committee Member)
Pages
156 p.
Subject Headings
Genetics
Keywords
NTDs
;
Lrp6
;
FA
;
MUTANTS
;
FA supplementation
;
Supplementation
;
Apob
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Nakouzi, G. A. (2009).
Genetic and Phenotypic Response of Neural Tube Defect Mouse Mutants to Folic Acid
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1246538783
APA Style (7th edition)
Nakouzi, Ghunwa.
Genetic and Phenotypic Response of Neural Tube Defect Mouse Mutants to Folic Acid.
2009. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1246538783.
MLA Style (8th edition)
Nakouzi, Ghunwa. "Genetic and Phenotypic Response of Neural Tube Defect Mouse Mutants to Folic Acid." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1246538783
Chicago Manual of Style (17th edition)
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Document number:
case1246538783
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Copyright Info
© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.