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 (Sox10^fl; 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 (Mitf^vga9) can rescue hair graying in Tg(DctSox10) animals. Surprisingly, Mitf^vga9 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 melanocyte stem cells (McSCs) that reside in the hair follicle are critical for generating the melanocytes that will differentiate and produce pigment for the hair during successive rounds of hair growth. The inappropriate maintenance of McSCs results in hair graying. Thus, our understanding of McSC biology is enhanced through the study of hair graying mouse models. We have discovered that sustained expression of the transcription factor, Sox10, in the melanocyte lineage results in loss of McSCs and consequently leads to premature hair graying. Through the use of mouse transgenics, we demonstrate that by changing Sox10 levels, melanocytes of the hair can preserve their ability to survive and produce normally pigmented hairs while also allowing a portion of them to fulfill the role of an undifferentiated McSC. We also discovered that Mitf, a downstream target of SOX10 and the master regulatory transcription factor for melanogenesis, appears to participate in McSC maintenance, perhaps by the negative regulation of SOX10-dependent processes. These observations raise the idea that adult stem cells, like McSCs, may rely on cell type specific transcription factors for their specification and survival, but that these transcriptions factors also have to be carefully regulated to maintain a stem cell fate.