Taylor, K.L., Lister, J.A., Zeng, Z., Ishizaki, H., Anderson, C., Kelsh, R.N., Jackson, I.J., and Patton, E.E. (2011) Differentiated melanocyte cell division occurs in vivo and is promoted by mutations in Mitf. Development (Cambridge, England). 138(16):3579-89.
Coordination of cell proliferation and differentiation is crucial for tissue formation, repair and regeneration. Some tissues, such as
skin and blood, depend on differentiation of a pluripotent stem cell population, whereas others depend on the division of
differentiated cells. In development and in the hair follicle, pigmented melanocytes are derived from undifferentiated precursor
cells or stem cells. However, differentiated melanocytes may also have proliferative capacity in animals, and the potential for
differentiated melanocyte cell division in development and regeneration remains largely unexplored. Here, we use time-lapse
imaging of the developing zebrafish to show that while most melanocytes arise from undifferentiated precursor cells, an
unexpected subpopulation of differentiated melanocytes arises by cell division. Depletion of the overall melanocyte population
triggers a regeneration phase in which differentiated melanocyte division is significantly enhanced, particularly in young
differentiated melanocytes. Additionally, we find reduced levels of Mitf activity using an mitfa temperature-sensitive line results
in a dramatic increase in differentiated melanocyte cell division. This supports models that in addition to promoting
differentiation, Mitf also promotes withdrawal from the cell cycle. We suggest differentiated cell division is relevant to melanoma
progression because the human melanoma mutation MITF4TΔ2B promotes increased and serial differentiated melanocyte division
in zebrafish. These results reveal a novel pathway of differentiated melanocyte division in vivo, and that Mitf activity is essential
for maintaining cell cycle arrest in differentiated melanocytes.