A Dual Role for SOX10 in the Maintenance of the Postnatal Melanocyte Lineage and the Differentiation of Melanocyte Stem Cell Progenitors

Abstract

During embryogenesis, the transcription factor, Sox10, drives the survival and differentiation of the melanocyte lineage. However, the role that Sox10 plays in postnatal melanocytes is not established. We show in vivo that melanocyte stem cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs remain undifferentiated. Sox10 knockout (Sox10fl; Tg(Tyr::CreER)) results in loss of both McSCs and differentiated melanocytes, while overexpression of Sox10 (Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to hair graying. This suggests that levels of SOX10 are key to normal McSC function and Sox10 must be downregulated for McSC establishment and maintenance. We examined whether the mechanism of Tg(DctSox10) hair graying is through increased expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf (Mitfvga9) can rescue hair graying in Tg(DctSox10) animals. Surprisingly, Mitfvga9 does not mitigate but exacerbates Tg(DctSox10) hair graying suggesting that MITF participates in the negative regulation of Sox10 in McSCs. These observations demonstrate that while SOX10 is necessary to maintain the postnatal melanocyte lineage it is simultaneously prevented from driving differentiation in the McSCs. This data illustrates how tissue-specific stem cells can arise from lineage-specified precursors through the regulation of the very transcription factors important in defining that lineage.

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

“…Fold increase over siCo Fold increase over shCo ARTICLE genes shown to be involved in melanoma formation turned out to be also important for normal melanocytes and benign hyperplasia cells 14,31,41,53 . In contrast, Ezh2 plays a unique tumour-specific role in melanoma and is not required for normal melanocyte function, in accordance with the strong upregulation of its expression during malignant melanoma progression.…”

“…Tyr::N-Ras Q61K animals and Ink4a-defficient mice have previously been described 14,34,61 . The Tyr::Cre ERT2 line 14,31,39 , Ezh2 lox animals 19,21 and R26R::LacZ mice 40 have been analyzed elsewhere. Mouse genotyping was performed according to a standard DNA isolation protocol 62 , followed by PCR using a Taq PCR Core Kit (201225, Qiagen) and primers indicated in (Supplementary Table 4).…”

“…Previously, high EZH2 expression has been described in biopsies of malignant melanoma in comparison to benign naevi 23,24 . To address whether changes in EZH2 expression affect cells of the melanocytic lineage rather than stromal cells in the tumour tissue, we performed co-staining of human cutaneous melanoma sections for EZH2 in combination with SOX10 or MART1-HMB45, all markers for the melanocytic lineage 14,[31][32][33] . In agreement with previous studies 23,24 , human primary melanomas and metastases displayed high EZH2 expression in cells of the melanocytic lineage compared with epidermal melanocytes and dermal naevus cells ( Fig.…”

“…3b). Hair greying is the phenotype predominantly arising upon interference with homeostasis of melanocyte stem cells in the bulge 31,41 , the permanent niche of epithelial and melanocyte stem cells in hair follicles 35,42 . However, hair pigmentation remained normal up to 1 year after Ezh2 depletion (Fig.…”

The biology of melanocyte and melanocyte stem cell

“…Some of these genes are also associated with the neural crest and melanocyte disorders in humans. Example of these genes include the transcription factors: Mitf [16][17][18], Sox10 [19,20]; Receptor tyrosine kinase Kit and its ligand KitL [21][22][23][24]; G-protein coupled endothelin-3 receptor/ligand pair [25,26]; Notch signaling [27]; small Rho GTPase Rac1 [28] and its activator P-Rex1 [29]; and actin bundling protein Fascin1 [30][31][32] and secreted protease of the ADAM family of the metalloproteinase ADAMTS20 [33].…”