27
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Author Summary

          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.

          Related collections

          Most cited references60

          • Record: found
          • Abstract: found
          • Article: not found

          Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.

          It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27(Kip1)-degradation such that reduced Mitf levels lead to a p27(Kip1)-dependent G1 arrest. Thus Mitf, via regulation of Dia1, can both inhibit invasiveness and promote proliferation. The results imply variations in the repertoire of environmental cues that determine Mitf activity will dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells through a dynamic epigenetic mechanism.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Dominant role of the niche in melanocyte stem-cell fate determination.

            Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.

              Mice with mutations at the microphthalmia (mi) locus have some or all of the following defects: loss of pigmentation, reduced eye size, failure of secondary bone resorption, reduced numbers of mast cells, and early onset of deafness. Using a transgenic insertional mutation at this locus, we have identified a gene whose expression is disrupted in transgenic animals. This gene encodes a novel member of the basic-helix-loop-helix-leucine zipper (bHLH-ZIP) protein family of transcription factors, is altered in mice carrying two independent mi alleles (mi and miws), and is expressed in the developing eye, ear, and skin, all anatomical sites affected by mi. The multiple spontaneous and induced mutations available at mi provide a unique biological resource for studying the role of a bHLH-ZIP protein in mammalian development.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                July 2013
                July 2013
                25 July 2013
                : 9
                : 7
                : e1003644
                Affiliations
                [1 ]Genetic Disease Research Branch, National Human Genome Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [2 ]Department of Genetics, University of Georgia, Athens, Georgia, United States of America
                [3 ]Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland
                [4 ]School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, United States of America
                [5 ]Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany
                University of Iceland, Iceland
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MLH KB OS RMH LS WJP. Performed the experiments: MLH KB OS RMH. Analyzed the data: MLH OS LS WJP. Contributed reagents/materials/analysis tools: RMH MW. Wrote the paper: MLH.

                Article
                PGENETICS-D-13-00321
                10.1371/journal.pgen.1003644
                3723529
                23935512
                b035692c-76b9-4f01-bc78-e1c86384365b
                Copyright @ 2013

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 4 February 2013
                : 1 June 2013
                Page count
                Pages: 14
                Funding
                Funding for the work presented in this study was provided by the National Human Genome Research Institute's Intramural Research Program at the National Institutes of Health (to WJP), and the Swiss National Science Foundation, National Research Program (NRP) 63, Promedica Foundation Chur, and the Swiss Cancer League (to OS, and LS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Organism Development
                Aging
                Organogenesis
                Stem Cells
                Adult Stem Cells
                Cell Differentiation
                Genetics
                Molecular Genetics
                Gene Regulation
                Animal Genetics
                Gene Function
                Gene Networks

                Genetics
                Genetics

                Comments

                Comment on this article