Abstract
Adult urodeles (salamanders) are unique in their ability to regenerate complex organs perfectly. The recently developed Accessory Limb Model (ALM) in the axolotl provides an opportunity to identify and characterize the essential signaling events that control the early steps in limb regeneration. The ALM demonstrates that limb regeneration progresses in a stepwise fashion that is dependent on signals from the wound epidermis, nerves and dermal fibroblasts from opposite sides of the limb. When all the signals are present, a limb is formed de novo. The ALM thus provides an opportunity to identify and characterize the signaling pathways that control blastema morphogenesis and limb regeneration. In the present study, we have utilized the ALM to identity the buttonhead-like zinc-finger transcription factor, Sp9, as being involved in the formation of the regeneration epithelium. Sp9 expression is induced in basal keratinocytes of the apical blastema epithelium in a pattern that is comparable to its expression in developing limb buds, and it thus is an important marker for dedifferentiation of the epidermis. Induction of Sp9 expression is nerve-dependent, and we have identified KGF as an endogenous nerve factor that induces expression of Sp9 in the regeneration epithelium.
Highlights
Urodele amphibians are unique among adult vertebrates in their ability to regenerate many of their body parts, including their limbs
We propose that there is a direct interaction between the nerve and the regeneration epithelium that induces keratinocyte dedifferentiation that is critical to successful limb regeneration
In order to distinguish between events that are common to both wound healing and regeneration, in contrast to those that are unique to regeneration, we investigated the expression of two marker genes (MMP-9 and Sp9) that are expressed in the early wound epidermis
Summary
Urodele amphibians are unique among adult vertebrates in their ability to regenerate many of their body parts, including their limbs. Denervation results in the loss of Dlx-3 expression in the AEC and regenerative failure, both of which are rescued by exogenous treatment with FGF2 (Mullen et al, 1996) We consider it likely that the function of nerves and the regeneration epithelium are coordinately regulated in limb regeneration, and that the WE/AEC are targets of the nerveassociated signaling pathway required for regeneration. By this view, the regeneration epithelium provides signaling that allows for the fibroblast–fibroblast interactions that control blastema growth and pattern formation. We propose that there is a direct interaction between the nerve and the regeneration epithelium that induces keratinocyte dedifferentiation that is critical to successful limb regeneration
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