Abstract(s)
Axolotls are unique among vertebrates in their ability to regenerate
tissues, such as limbs, tail and skin. The axolotl limb is the most
studied regenerating structure. The process is well characterized
morphologically; however, it is not well understood at the molecular
level. We demonstrate that TGF-β1 is highly upregulated during
regeneration and that TGF-β signaling is necessary for the
regenerative process. We show that the basement membrane is not
prematurely formed in animals treated with the TGF-β antagonist SB-
431542. More importantly, Smad2 and Smad3 are differentially
regulated post-translationally during the preparation phase of limb
regeneration. Using specific antagonists for Smad2 and Smad3 we
demonstrate that Smad2 is responsible for the action of TGF-β during
regeneration, whereas Smad3 is not required. Smad2 target genes
(Mmp2 and Mmp9) are inhibited in SB-431542-treated limbs,
whereas non-canonical TGF-β targets (e.g. Mmp13) are unaffected.
This is the first study to show that Smad2 and Smad3 are differentially
regulated during regeneration and places Smad2 at the heart of
TGF-β signaling supporting the regenerative process.