Craniofacial birth defects are associated with significant morbidity and mortality and can be highly variable in their severity and presentation. One key regulator of proper craniofacial development is the action of bone morphogenetic proteins (BMPs). Twisted gastrulation (TWSG1) modulates BMP signaling and the mutation of TWSG1 in mice results in a range of mild to severe birth defects, including forms of holoprosencephaly and dysgnathia. TWSG1 is a glycoprotein with sugar modifications which are essential for proper BMP binding and normal activity of TWSG1. In the mouse TWSG1 protein these sugars are attached in the region of the protein encoded by exon 4. The variable phenotypes resulting from exon 4 deletion <italic>(Twsg1<super>-/-</super>)</italic> in mice are associated with distinct sets of transcriptional changes compared to wild type, even for apparently unaffected embryos. The action of p53 plays a key role in the manifestation of severe birth defects in <italic>Twsg1<super>-/-</super></italic> mice, correlating with previously observed increases in apoptosis. Genetic deficiency of p53 is associated with reduced defects in <italic>Twsg1<super>-/-</super></italic> mice. Some of the craniofacial defects in <italic>Twsg1<super>-/-</super></italic> mice, specifically defects associated with the first branchial arch but not holoprosencephaly or midline defects, can be limited by maternal dietary supplementation with methyl donor compounds including folate, choline, betaine and vitamin B12. Previous pregnancy increases the risk of birth defects in <italic>Twsg1<super>-/-</super></italic> mice. A mouse model of TWSG1 over-expression has been generated to further investigate the action of this gene and provide a reagent for future experiments examining the role of TWSG1 in development.
University of Minnesota Ph.D. dissertation. February 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Anna Petryk and Michael B. O'Connor. 1 computer file (PDF); ix, 137 pages.
Billington, Charles John.
Mechanisms and prevention of variable craniofacial defects in Twisted gastrulation mutant mice.
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