Browsing by Subject "Twisted gastrulation"
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Item Development and Cancer: The role of Twisted Gastrulation in mammary gland development and in cancer.(2014-11) Forsman, CynthiaIt is becoming increasingly clear that the molecular mechanisms that maintain and promote pluripotency during development reemerge as important mediators of tumorigenicity. Bone morphogenetic proteins (BMPs) and their modulators play numerous and diverse roles during development and, as recent evidence suggests, in cancer. One key modulator of BMP signaling during craniofacial and mammary gland development is the glycoprotein Twisted gastrulation-1 (TWSG1). The loss of Twsg1 results in craniofacial malformations, a delay in mammary gland development and lactation defects. TWSG1 has been shown to function both in the positive and negative regulation of BMP signaling. This dual nature may be explained first by TWSG1's ability to bind BMPs and prevent their interaction with receptors. This function is similar to other extracellular BMP antagonists such as Noggin and Gremlin. Additionally, the TWSG1: BMP ligand complex can be joined by Chordin and when this tripartite complex is formed Tolloid can cleave Chordin releasing BMPs into the extracellular space at some concentration. The timing of this release and availability of other extracellular partners may, in part, dictate the influence TWSG1 has on BMP signaling. Interestingly, TWSG1 overexpression has been detected in tumors of tissues in which it also plays a key role in development such as the oral cavity and breast. It therefore provides an interesting model by which to investigate the tenuous balance between pluripotency and tumorigenesis.Item Mechanisms and prevention of variable craniofacial defects in Twisted gastrulation mutant mice(2013-02) Billington, Charles JohnCraniofacial 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 (Twsg1-/-) 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 Twsg1-/- mice, correlating with previously observed increases in apoptosis. Genetic deficiency of p53 is associated with reduced defects in Twsg1-/- mice. Some of the craniofacial defects in Twsg1-/- 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 Twsg1-/- 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.