The regeneration of damaged organs may eventually be achieved with stem cell-mediated therapy. In some models, adult progenitor cells are carefully directed to regenerate patterned, functional tissue structures through complex signaling pathways. Many of the pathways that promote regeneration also contribute to cancer formation. The selective ability to induce regeneration of tissue without causing cancer requires more knowledge of the signals that mediate these two processes. Ras is an important regulator of cell growth and is mutated in tumors of many cancer patients. Ras regulation of tissue regeneration is not well understood, which impedes the potential for stem cell therapy for regenerative medicine.
Zebrafish are able to regenerate amputated fins that have a normal striped pattern. The ability of the stripe-forming melanocytes to faithfully regenerate in the correct position during the complex process of fin regeneration provides a useful model to dissect the pathways that direct stem cells. Little is known about the participation of Ras in zebrafish fin regeneration.
When a zebrafish loses its fin, it replaces the lost bone and soft tissues, and reestablishes its characteristic pigment stripes from precursor melanocytes. To determine the effect of Ras on regeneration, the authors use a fin amputation and regeneration zebrafish model in which they manipulate Ras activity during fin regeneration. Elevated Ras activity causes dose-dependent expansion of pigmented melanocytes and melanocyte precursors. Active Ras also rescues pigmentation during fin regeneration in normally unpigmented mutants that lack functional c-Kit, which is a proto-oncogenic receptor tyrosine kinase that is predicted to be an upstream regulator of Ras. These findings position Ras as a key downstream mediator of c-Kit signaling during fin regeneration and demonstrate that Ras activity supports melanocyte precursor proliferation in the zebrafish fin during regeneration.
Implications and future directions
This work demonstrates a central role for Ras in the zebrafish fin pigmentation model of regeneration. During Ras-induced hyperpigmentation, melanocytes occupy the correct niche within the fin rays and then resolve normally into stripes after experimental activation of Ras is discontinued. It will be interesting to develop models to analyze how progenitor proliferation is controlled in other cell lineages, and to determine how cell specialization affects the process of fin regeneration. Since Ras is important to both regeneration and cancer formation, it should be useful to identify the molecular events that prevent melanocyte hypercellularization in fin regeneration. Understanding the roles of Ras and other signaling molecules in stem and progenitor cell regulation should promote the potential use of stem cells in the therapeutic regeneration of human tissues.