Gpnmb is a melanoblast-expressed, MITF-dependent gene.
Gpnmb is a melanoblast-expressed, MITF-dependent gene.
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DOI：
10.1111/j.1755-148x.2008.00518.x
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发表时间：
2009-02
影响因子：
4.3
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Loftus SK;Antonellis A;Matera I;Renaud G;Baxter LL;Reid D;Wolfsberg TG;Chen Y;Wang C;NISC Comparative Sequencing Program;Prasad MK;Bessling SL;McCallion AS;Green ED;Bennett DC;Pavan WJ
表达谱分析将Gpnmb与已知的色素基因、Tyrp1、Dct和Si聚类。在发育过程中，Gpnmb的表达模式与Mitf、Dct和Si相似，在Mitf突变动物中表达量大幅降低。与Dct和Si不同，Gpnmb在sox10缺陷胚胎的尾侧黑色素母细胞离散群体中仍然表达。为了了解Gpnmb的转录调控，我们对2460,048个一致的MITF结合位点进行了全基因组注释，并将其与Gpnmb位点的进化保守基因组序列进行了交叉比对。其中一个保守元件GPNMB-MCS3含有两个MITF共识位点，显著提高了黑色素细胞中荧光素酶的活性，足以驱动体内黑色素母细胞的表达。删除5 ' -most MITF共识位点显著降低增强子活性，表明该位点在Gpnmb转录调控中起重要作用。未来对Gpnmb基因座的分析将有助于深入了解黑素细胞的转录调控，Gpnmb的表达可作为分析黑素细胞发育和疾病进展的标志物。利用小鼠黑素细胞系进行基因表达谱的比较分析，为探索黑素细胞发育和色素细胞功能的遗传成分提供了强有力的资源。通过表达数据，我们发现Gpnmb是早期黑色素细胞发育的新标志物。我们发现Gpnmb在体内的表达依赖于Mitf，并标记了一组独特的不依赖于sox10的黑色素母细胞。我们在Gpnmb位点发现了一个89碱基对进化保守的基因组序列，该序列可以增强黑素细胞的表达，并测试了MITF E-box共识序列是否参与黑素细胞限制性表达。Gpnmb和本研究中确定的基因组将为了解参与黑素细胞发育和疾病的遗传成分提供宝贵的资源。
Expression profile analysis clusters Gpnmb with known pigment genes, Tyrp1, Dct, and Si. During development, Gpnmb is expressed in a pattern similar to Mitf, Dct and Si with expression vastly reduced in Mitf mutant animals. Unlike Dct and Si, Gpnmb remains expressed in a discrete population of caudal melanoblasts in Sox10-deficient embryos. To understand the transcriptional regulation of Gpnmb we performed a whole genome annotation of 2,460,048 consensus MITF binding sites, and cross-referenced this with evolutionarily conserved genomic sequences at the GPNMB locus. One conserved element, GPNMB-MCS3, contained two MITF consensus sites, significantly increased luciferase activity in melanocytes and was sufficient to drive expression in melanoblasts in vivo. Deletion of the 5’-most MITF consensus site dramatically reduced enhancer activity indicating a significant role for this site in Gpnmb transcriptional regulation. Future analysis of the Gpnmb locus will provide insight into the transcriptional regulation of melanocytes and Gpnmb expression can be used as a marker for analyzing melanocyte development and disease progression. Comparative analysis of gene expression profiles using melanocyte lines derived from mice provides a powerful resource to explore genetic components of melanocyte development and pigment cell function. Using expression data, we identified Gpnmb as a new marker for early melanoblast development. We show that Gpnmb is dependent on Mitf for in vivo expression and marks a unique set of Sox10-independent melanoblasts. We identified an 89 basepair evolutionarily conserved genomic sequence at the Gpnmb locus that can enhance expression in melanocytes and tested MITF E-box consensus sequences for their involvement in melanocyte-restricted expression. Gpnmb and the panel of genes identified in this study will be valuable resources for understanding the genetic components involved in melanocyte development and diseases.