Figure 9

Contribution of innervation to fin regeneration. a) Illustration of the putative role of nerves in zebrafish fin regeneration. The WE is formed after fin amputation, in a process that is independent of nerves. Innervation may be important to the subsequent thickening of the WE and the establishment of the AEC, which contributes to the formation and outgrowth of the blastema and to the progression of the regenerative process. The role of nerves may be to release factor(s) (“factor x”) that regulate the expression of target genes in the WE, such as pea3, fgf24 and lef1, which are important to the thickening and maintenance of the WE and to the communication established with the underlying cells. At the same time nerves may be involved in the inhibition of wnt5b in the WE, as well as in the pathways that lead to apoptosis. “Factor x” may also be directly released by nerves into the stump to induce cell proliferation and dedifferentiation. b) Illustration of the cellular and molecular changes occurred upon fin denervation. In the absence of innervation fins do not establish a functional AEC and several signalling pathways are affected. Wnt5b, an inhibitor of Wnt signalling and regeneration, is upregulated at 0.5 dpa, but is downregulated at 1 dpa. During this period krt8 and pea3, which are essential to WE maintenance, as well as fgf24 and lef1, important for the communication established with the underlying cells, are downregulated. At the same time, apoptosis activity is increased in the WE. The Fgf signalling molecules fgfr1, msxc, and mkp3 are upregulated, while fgf20a is downregulated. Shh is early downregulated at 0.5 dpa, but is then upregulated at 1 dpa. These signalling defects result in a breakdown of communication with mesenchymal cells, and impairment of the formation of the blastema and fin regeneration.