83formed the neonatal blastema is similar to the adult blastema, composed of
undifferentiated mesenchymal cells with a relatively high proliferative index and
reduced vascularity. Re-differentiation of the digit tip occurs in a proximal to distal
manner by direct ossifi cation as it does in adults. Regeneration of the fetal digit tip
is, however, considerably different. The fetal mouse digit tip is largely undifferenti-
ated at the time of amputation , wound closure and blastema formation occurs rap-
idly, and the regeneration process is completed over a very short timeframe. While
uniquely different from post-natal and adult regeneration, the process of fetal regen-
eration can occur ex vivo making it an attractive model to experimentally dissect the
regenerative response [ 11 ].
5.3 Regenerative Failure and Induced Regeneration
Mouse digit tip regeneration is a valuable model for mammalian regeneration , but it
also has added value because the response is amputation level specifi c; amputation
at any digit or limb level proximal to the digit tip fails to regenerate. Uncovering
critical events important for the endogenous regenerative response can be studied
during the healing events associated with regenerative failure. In recent years strate-
gies to induce regeneration from proximal amputations have been successful, thus
demonstrating for the fi rst time, that mammalian regeneration can be specifi cally
induced and, in some cases, provide evidence that events associated with the non-
regenerating healing response actively inhibit the regenerative process. These fi nd-
ings are critically important because they demonstrate the existence of a regenerative
potential that is actively repressed in normally non-regenerative injuries that can be
activated by targeted treatments during wound healing.
One of the fi rst successful demonstrations of induced mammalian regenerationfocused on the importance of Bone Morphogenetic Proteins (BMPs) , members of
the TGFβ superfamily of signaling molecules, signaling in digit tip regeneration
[ 12 ]. Studies of the regenerating fetal digit demonstrated that expression of the
homeobox-containing gene Msx1 and Bmp4 were co-expressed in the digit tip and
were re-expressed during the regenerative response [ 11 , 13 ]. Moreover, the expres-
sion domain of Msx1 correlates with regeneration permissive amputation levels, and
amputation studies of Msx1 mutant digits failed to regenerate, thus providing evi-
dence that the Msx1 gene is functionally required for a regenerative response [ 11 ].
In other studies, Msx1 was shown to repress cell differentiation during embryonic
development [ 14 ], and was implicated in the control of tail regeneration in the
Xenopus tadpole [ 15 ]. In addition, Msx1 activity has been linked to the induction of
de-differentiation of mammalian myotubes in vitro [ 16 ], suggesting that its activity
is essential for a regenerative response. Using the digit regeneration defect , Han
et al. [ 11 ] discovered that treatment with exogenous BMP4 was able to rescue the
Msx1 regeneration phenotype in a dose dependent manner. This resulted in enhanced
cell proliferation, the re-expression of a number of digit specifi c genes, and the
restoration of the digit tip. To test if BMP signaling was critical for wildtype digit
5 Digit Regeneration in Mammals