A chemical-genetic approach to melanocyte stem cells: a novel role for the Prl-3 phosphatase


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Elizabeth Patton
Edinburgh Cancer Research Centre, Edinburgh, UK

Abstract

Melanocytes are specialised skin cells that produce pigment, and protect the skin from the cancerous effects of UV-irradiation. Melanoma is an aggressive, rapidly invasive cancer of the melanocyte, and UV-light is the major environmental risk factor for melanoma, especially in fair-skinned populations. Melanoma may be maintained by stem cells that have the capacity to proliferate, differentiate, and sustain tumour formation. In an effort to further understand the aetiology of melanoma, we aim first to understand the biology of normal melanocyte ontogeny and regeneration; namely the mechanisms by which melanocytes develop from melanocyte stem cells (MSCs), how they proliferate and migrate in a whole organism.

We have identified a small molecule (BIO1E7) that kills differentiated melanocytes, and prevents the ability of the MSC to regenerate differentiated melanocytes. In a chemical screen for suppressors of the Bio1E7-MSC activity in zebrafish embryos, we have identified small molecules that enhance melanocyte regeneration after Bio1E7 treatment. We find that chemical inhibition of Prl-3 can enhance melanocyte regeneration from undifferentiated melanocyte precursors in embryos that have ablated melanocytes, and during adult tail fin regrowth. Prl-3 is a tyrosine phosphatase that is transcriptionally regulated by the p53 tumour-suppressor protein, and has been linked to modulation of the MAPK and PTEN pathways. Morpholino knockdown of Prl-3 enhances regeneration in BIO1E7 treated embryos, confirming the specificity of the PRL3 inhibitor treatment. We are now taking advantage of several genetic and transgenic lines, in combination with small molecule treatments, to further explore the function of Prl-3 in melanocyte regeneration and melanoma development.