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Brittney R. Royal Research Article Summary BIOL 501-Senior Project Author, Title, Journal, Year, Volume, Pages Key Terms Introduction/ Purpose J. Knobloch, J.D. Shaughnessy, U. Ruther, “Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway,” The FASEB Journal, vol 21, no. 7, pp. 1410-1421, 2007 Research Question/Hypothesis Materials & Methods - Many tissues and organs like eyes and heart, for example, are affected by thalidomide during embryonic development. - However, variable limb truncations such as amelia (absence of limbs) and phocomelia (proximal limb truncations) are most frequent. - Thalidomideinduced limb defects and microphthalmia (small eyes) are caused by an oxidative stress mediated upregulation of Bmp - Current hypotheses presume that thalidomide interferes with limb outgrowth by inducing oxidative stress in the limb mesenchyme and/or by inhibiting angiogenesis (4 , 5). - However, the molecular pathways essential for mediating thalidomide teratogenicity remain unknown. - Chicken embryos and drug treatment - Primary cells and drug treatment - Cartilage staining - Plasmids - TOP/FOPflash assay - Subcellular localization - Detection of transcriptional activity - Detection of cell death - Statistical analyses Results - Thalidomide induces limb truncations and microphthalmia in chicken embryos - Thalidomide induces Dkk1 and Bmp expression and apoptosis in limb buds - Blocking of Bmps, Dkk1, or Gsk3ß counteracts thalidomide-induced cell death - Thalidomide inhibits ß-catenin activity - Thalidomideinduced ROS formation is a prerequisite for enhanced Bmp expression and inhibition of Wnt signaling - Inhibition of Bmps, Conclusion/Discussion - Thalidomide-induced PCD, limb truncations, and microphthalmia are a result, at least in part, of a cascade of events that includes ROS generation, enhanced Bmp signaling, activation of theWnt antagonist Dkk1, and suppression of canonical Wnt/ß-catenin signaling. - Thalidomide-induced embryopathy could be traced to increased level of ROS - The diminished ß-catenin activity ultimately leads to increased PCD that is responsible for the limb and eye defects during embryonic development. - The resulting downregulation of Wnt/ß-catenin signaling is important for the teratogenic properties of the drug. Brittney R. Royal Research Article Summary BIOL 501-Senior Project signaling. Dkk1, or Gsk3ß counteracts thalidomide-induced teratogenicity