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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