A conserved transcriptional enhancer that specifies Tyrp1 expression to melanocytes
A conserved transcriptional enhancer that specifies Tyrp1 expression to melanocytes
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DOI：
10.1016/j.ydbio.2006.05.011
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发表时间：
2006-10-15
影响因子：
2.7
通讯作者：
Beermann, Friedrich
中科院分区：
文献类型：
--
作者：
Murisier, Fabien;Guichard, Sabrina;Beermann, Friedrich
哺乳动物的色素细胞来自两个不同的谱系：黑素细胞起源于神经脊，而视网膜色素上皮(RPE)细胞起源于发育中的前脑的视杯。以前的研究表明，色素沉着基因在黑素细胞和RPE中受不同的调控网络控制。酪氨酸酶相关家族基因Tyrp1的启动子被证明只驱动可检测到的转基因表达到RPE，尽管该基因也在黑素细胞中表达，正如Tyrp1突变小鼠所明显的那样。这表明RPE中负责Tyrp1基因表达的调控元件不足以在黑素细胞中表达。因此，我们寻找了一个假定的黑素细胞特异性调控序列，并证明了包含Tyrp1基因及其周围序列的细菌人工染色体(BAC)能够靶向黑素细胞的转基因表达，并挽救Tyrp1(B)(棕色)表型。该BAC含有几个高度保守的非编码序列，可能代表新的调控元件。我们进一步关注了位于-15kb的序列，细胞培养和转基因小鼠实验表明，该序列是黑素细胞特异性增强子。此外，我们还发现转录因子Sox10可以激活这个保守的增强子。远端Tyrp1调控元件的存在，指定了黑素细胞的特异性表达，支持了单独的调控序列可以调节黑素细胞和RPE中差异基因表达的想法。(C)2006 Elsevier Inc.保留所有权利。
Pigment cells of mammals originate from two different lineages: melanocytes arise from the neural crest, whereas cells of the retinal pigment epithelium (RPE) originate from the optic cup of the developing forebrain. Previous studies have suggested that pigmentation genes are controlled by different regulatory networks in melanocytes and RPE. The promoter of the tyrosinase-related family gene Tyrp1 has been shown to drive detectable transgene expression only to the RPE, even though the gene is also expressed in melanocytes as evident from Tyrp1-mutant mice. This indicates that the regulatory elements responsible for Tyrp1 gene expression in the RPE are not sufficient for expression in melanocytes. We thus searched for a putative melanocyte-specific regulatory sequence and demonstrate that a bacterial artificial chromosome (BAC) containing the Tyrp1 gene and surrounding sequences is able to target transgenic expression to melanocytes and to rescue the Tyrp1(b) (brown) phenotype. This BAC contains several highly conserved non-coding sequences that might represent novel regulatory elements. We further focused on a sequence located at -15 kb, which we identified as a melanocyte-specific enhancer as shown by cell culture and transgenic mice experiments. In addition, we show that the transcription factor Sox10 can activate this conserved enhancer. The presence of a distal Tyrp1 regulatory element, which specifies melanocyte-specific expression, supports the idea that separate regulatory sequences can mediate differential gene expression in melanocytes and RPE. (c) 2006 Elsevier Inc. All rights reserved.