New Perspectives on Melanoma_ The Role of PAX3

By contrast mitf promotes melanoblast survival during

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Unformatted text preview: natal skin [46‐48], whereas in human skin they persists postnatally [17,49‐51]. 5 Chapter I – Thesis Overview Regulation of melanocyte development: Role of Pax3 during embryogenesis Pax3 is one of nine members of the paired box (Pax) family of transcription factors, which have all been implicated in regulation of organogenesis and described as key factors in stem cell maintenance during development and maturation (reviewed in [52,53]). Pax3 is involved in development of the central and peripheral nervous system, skeletal muscle and cardiac tissue, gastrointestinal enteric ganglia, and skin melanocytes. Pax3 is the first regulator of neural crest specification [10,11,54]. Its expression is observed in precursor cells prior to neurulation [17]. During neurulation, Pax3 plays a crucial antiapoptotic role, regulating proper development and closure of the neural tube, via inhibition of p53 (tumour protein p53)‐mediated apoptosis, and activation of its targets, BAX (BCL2­associated X protein) and HDM2 (Mdm2 p53 binding protein homologue) [55,56]. Here Pax3 is also crucial for proper migration of cells, via direct regulation of transcription of both TGFα (transforming growth factor α) and TGFβ (transforming growth factor β) [57,58]. TGFβ signalling pathways are involved in remodelling of the extracellular matrix, and cell cytoskeleton required for cellular migration [58‐61]. Mutations or knock out models of either Pax3, p53 or TGFβ, result in neural tube defects, confirming that Pax3‐mediated regulation of cell survival and migration are crucial at this stage of development [55,62]. Following neural tube closure, expression of Pax3 continues in a number of progenitor cells, including those in the dorsal root ganglion, in the cells entering the migratory pathway in the dermomyotome, myoblasts, and in developing melanoblasts throughout their development (Figure 1.1.2.) [17,63]. Pax3 is crucial for melanoblast specification, being at the very pinnacle of the hierarchy of melanocyte‐specific gene regulators, directly activating other key...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.

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