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SOX10 在维持产后黑素细胞谱系和黑素细胞干细胞祖细胞分化中的双重作用。

A dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and the differentiation of melanocyte stem cell progenitors.

机构信息

Genetic Disease Research Branch, National Human Genome Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

出版信息

PLoS Genet. 2013;9(7):e1003644. doi: 10.1371/journal.pgen.1003644. Epub 2013 Jul 25.

DOI:10.1371/journal.pgen.1003644
PMID:23935512
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3723529/
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.

摘要

在胚胎发生过程中,转录因子 Sox10 驱动黑素细胞谱系的存活和分化。然而, Sox10 在出生后黑素细胞中的作用尚未确定。我们在体内显示黑素细胞干细胞 (McSCs) 和更分化的黑素细胞表达 SOX10 ,但 McSCs 仍未分化。 Sox10 敲除 ( Sox10(fl); Tg(Tyr::CreER)) 导致 McSCs 和分化的黑素细胞丢失,而过表达 Sox10 ( Tg(DctSox10)) 导致过早分化和 McSCs 丢失,导致头发变白。这表明 SOX10 的水平对正常 McSC 功能至关重要,并且 Sox10 必须下调以建立和维持 McSC。我们通过询问 Mitf ( SOX10 的靶标) 的表达是否增加来检查 Tg(DctSox10) 头发变白的机制,Mitf 缺失 ( Mitf(vga9) ) 是否可以挽救 Tg(DctSox10) 动物的头发变白。令人惊讶的是, Mitf(vga9) 并没有减轻但加剧了 Tg(DctSox10) 头发变白,这表明 MITF 参与了 McSCs 中 Sox10 的负调控。这些观察结果表明,虽然 SOX10 对于维持出生后黑素细胞谱系是必需的,但它同时被阻止在 McSCs 中驱动分化。这些数据表明,组织特异性干细胞如何通过调节对定义该谱系非常重要的转录因子,从谱系指定的前体中产生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/b66ac81448f4/pgen.1003644.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/d271876283bc/pgen.1003644.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/6a6c0ab1e14d/pgen.1003644.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/9fef77fea4d5/pgen.1003644.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/0fb6a956d4f6/pgen.1003644.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/fda2e41ecd83/pgen.1003644.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/b66ac81448f4/pgen.1003644.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/d271876283bc/pgen.1003644.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/310c112d42e3/pgen.1003644.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/6a6c0ab1e14d/pgen.1003644.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/9fef77fea4d5/pgen.1003644.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/0fb6a956d4f6/pgen.1003644.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/fda2e41ecd83/pgen.1003644.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e3/3723529/b66ac81448f4/pgen.1003644.g007.jpg

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