New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: This study is aimed therefore at clarifying the role/s of PAX3 in normal melanocytes and in melanoma cells. To achieve this aim we performed a detailed analysis of PAX3 expression in normal skin and in various melanocytic lesions, and identified downstream PAX3‐regulated targets and associated pathways in melanocytes and in melanoma cells. Key differences, if any, in PAX3 function between these two cell types, are likely to provide strategic clues to the process of melanoma‐genesis. 3 Chapter I – Thesis Overview ii. LITERATURE REVIEW In order to uncover mechanisms of melanoma development and progression, we first need to understand the regulatory mechanisms acting in normal cells from which melanoma originates. This literature review is focused firstly on melanocytes, describing their development, function, key regulatory mechanisms, and the involvement of PAX3 in these processes. The review then focuses on melanoma and on PAX3‐regulated pathways driving its development and progression. 1. Melanocytes: Development and function Melanocytes are speed pigment producing cells located in the skin, brain, inner ear and choroid layer of the eye (pigmented cells in the retinal pigmented epithelium are not of neural crest origin, rather they develop from locally derived neural epithelium of the optic cup) [35]. Human melanocytes of the skin are located in the hair follicles (termed follicular melanocytes) and at the epidermal‐ dermal border, above the basal lamina (termed interfollicular or epidermal melanocytes). In contrast, mouse melanocytes are generally located in the hair follicles, except for the hairless parts of the body (tail, nose and ears) where they are located in the epidermis [36]. 1.1. Melanocyte development: From neural crest through melanoblasts to melanocytes Melanocytic origin and embryonic development Melanocytes originate from the neural crest in early developing embryos. The neural crest is an ectodermal derivative of vertebrate embryos, which produces a transient population of multipotent progenitor cells (Figure 1.1.1.A). These cells arise at the lateral edge of the neural plate, adjacent to...
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