New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: est specification [10,11], and later for expansion of committed melanoblasts formed early in development [12]. Mice that are homozygous for a mutation in Pax3 show greatly reduced numbers of melanoblasts but the cells are able to migrate to characteristic locations along the migratory pathway [12], suggesting a role in specification and proliferation of melanoblast precursors but not in the migration process, at least at this stage of melanoblast/melanocyte development. 36 Chapter II – Medic and Ziman, 2009 Sox10 is a transcription factor critical for the survival of neural crest cell progenitors and proper differentiation of melanocytes [180]. Mice that are homozygous for a mutation in Sox10, lack Mitf‐ and Dct‐expressing cells and have reduced numbers of Kit‐expressing cells, due to the essential role that Sox10 plays in activating the promoters of these genes [64,181,182]. Both Pax3 and Sox10 are required, and precede expression of the transcriptional regulator Mitf [64,65,181]. Mitf is crucial for melanoblast survival during and immediately following migration from the dorsal neural tube to the migration staging area; mice that are heterozygous for a mutation in the Mitf gene show diminished numbers of melanoblasts but only in early stages of development, whereas during the migratory phase this number increases rapidly. Mitfmi/Mitfmi mutant melanoblasts do not undergo dorsolateral migration (either they are not capable of migration or they don’t survive) [12]. Mitf also has a role in melanocyte stem cell survival in adult tissue, since mice homozygous for Mitfmi­vit (vitiligo spontaneous mutation) exhibit vitiligo, characterised by initially normal pigmentation which is lost during thenext hair follicle cycle [183,184]. Dct encodes a melanogenic enzyme which marks the emergence of early melanoblasts. Several transcription factors are involved in the regulation of Dct expression including Pax3, Sox10, Mitf and Lef1 which all bind directly to the Dct promoter and act together to activate transcription [19,72,185,186]...
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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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