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New Perspectives on Melanoma_ The Role of PAX3

Mitfmimitfmi mutant melanoblasts do not undergo

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Unformatted text preview: melanoma remains unclear. By clarifying its functions during embryonic and adult melanocyte development we provide insights into its roles in melanoma. 33 Chapter II – Medic and Ziman, 2009 Figure 2.1. Schematic representation of human PAX3 mRNA splice variants. (A) shows the exons (E) (E1 to E9) and introns and their respective sizes. (B) shows the structure of alternative transcripts a, b, c, d, e, g, and h. Filled boxes depict sequences retained in mature mRNA, clear boxes represent sequences spliced out and patterned boxes are non‐transcribed sequences; the vertical blue lines represent the transcription start sites and the vertical red lines and asterisks (*) indicate the positions of the alternate stop codons. This representation is based upon current information for human PAX3 mRNA available on NCBI (Evidence Viewer Tool). Melanocyte development during embryogenesis Mammalian skin melanocytes originate from neural crest cells formed early in developing embryos. Neural crest cells are ectodermal derivatives characteristic of vertebrate embryos and represent a transient population of multipotent progenitor cells arising at the lateral edge of the neural plate adjacent to the non‐ neural ectoderm. After delamination and migration from the neuroepithelium, 34 Chapter II – Medic and Ziman, 2009 these cells differentiate and contribute to various tissues, such as pigment cells, neurons, bone and endocrine cells, smooth muscles and craniofacial cartilage [37]. As the cells divide and migrate, multipotent neural crest cells acquire more lineage‐specific phenotypes, including that of melanoblasts, which upon reaching its destination in the epidermis terminally differentiate into melanocytes. Pathways crucial for the regulation of melanocyte development have been detailed in mouse studies. Key genes regulating these pathways are those encoding transcription factors Pax3 (Paired box 3), Sox10 (Sry‐like HMG box 10) and Mitf (Microphthalmia transcription factor) (Figure 2.2A). Pax3 is first expressed in neural crest precursors as they differentiate from the neural ectoderm [10,54]; expr...
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