Analysis of SOX10 Function in Neural Crest-Derived Melanocyte Development: SOX10-Dependent Transcriptional Control of Dopachrome Tautomerase

Abstract

SOX10 is a high-mobility-group transcription factor that plays a critical role in the development of neural crest-derived melanocytes. At E11.5, mouse embryos homozygous for the Sox10(Dom) mutation entirely lack neural crest-derived cells expressing the lineage marker KIT, MITF, or DCT. Moreover, neural crest cell cultures derived from homozygous embryos do not give rise to pigmented cells. In contrast, in Sox10(Dom) heterozygous embryos, melanoblasts expressing KIT and MITF do occur, albeit in reduced numbers, and pigmented cells eventually develop in nearly normal numbers both in culture and in vivo. Intriguingly, however, Sox10(Dom)/+ melanoblasts transiently lack Dct expression both in culture and in vivo, suggesting that during a critical developmental period SOX10 may serve as a transcriptional activator of Dct. Indeed, we found that SOX10 and DCT colocalized in early melanoblasts and that SOX10 is capable of transactivating the Dct promoter in vitro. Our data suggest that during early melanoblast development SOX10 acts as a critical transactivator of Dct, that MITF, on its own, is insufficient to stimulate Dct expression, and that delayed onset of Dct expression is not deleterious to the melanocyte lineage.

SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

“…All of these proteins are essential for the full differentiation of melanocytes and are directly involved in melanin synthesis. SOX10 also acts as a critical transactivator of DCT, which MITF, on its own, is insufficient to stimulate (5)(6)(7).…”

Complementation of melanocyte development in SOX10 mutant neural crest using lineage‐directed gene transfer

“…3A). To further characterize the identity of TVA cells, cultured NC cells were fixed 5 days after treatment with RCAS-GFP and stained with antibody to the NC stem cell marker SOX10 (Paratore et al, 2001;Potterf et al, 2001;Kim et al, 2003). The majority of GFP-positive cells were also positive for SOX10 expression (Fig.…”

“…Analysis of NC cultures isolated from Sox10 Dom /Sox10 Dom embryos determined that fully differentiated pigmented melanocytes are absent in 2-week cultures (Potterf et al, 2001). We wanted to determine whether the RCAS-TVA lineage-directed gene transfer system could be used to rescue melanocyte differentiation in the NC cell cultures by introducing Sox10 into Sox10 LacZ /Sox10 LacZ NC cells.…”

“…For double immunolabeling, SOX10 (Potterf et al, 2001) and hemagglutinin (HA; Covance) were diluted 1:200 and added to the cells for incubation at 37°C for 60 min, respectively. The primary antibodies were revealed with rhodamine isothiocyanate-coupled goat anti-rabbit (Fab)2 or fluorescein isothiocyanate-coupled goat antimouse (Fab)2.…”

“…The analysis of Sox10 gene function using mutant mammalian models is hampered because Sox10 Dom /Sox10 Dom and Sox10 LacZ /Sox10 LacZ embryos die before birth (Lane andLiu, 1984, Britsch et al, 2001). Although it has been demonstrated that Sox10 is critical for survival of several NC-derived lineages (Southard-Smith et al, 1998;Britsch et al, 2001;Potterf et al, 2001) and several downstream target genes have been identified Lang et al, 2000;Lee et al, 2000;Peirano et al, 2000;Potterf et al, 2000Potterf et al, , 2001Bondurand et al, 2001;Britsch et al, 2001), the functional roles of SOX10 in the development of NC-derived lineages is not completely understood.…”