Neural crest patterning:: autoregulatory and crest-specific elements co-operate for Krox20 transcriptional control
Neural crest patterning:: autoregulatory and crest-specific elements co-operate for Krox20 transcriptional control
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DOI：
10.1242/dev.00318
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发表时间：
2003-03-01
期刊：
影响因子：
4.6
通讯作者：
Frain, M
中科院分区：
文献类型：
--
作者：
Ghislain, J;Desmarquet-Trin-Dinh, C;Frain, M
神经嵴图式构成颅面结构形态发生控制的一个重要因素。Krox 20是一种转录因子基因，在分节后脑的发育中起着关键作用，Krox 20在菱体（r）3和5中表达，并在从r5向第三鳃弓迁移的神经嵴细胞流中表达。我们研究了Krox 20特异性神经嵴表达的基础，并鉴定了顺式作用增强子元件（NCE）。位于小鼠、人和鸡之间保守的基因上游26 kb处，并且可以在转基因小鼠中重现Krox 20神经嵴模式。增强子的功能解剖揭示了两个保守的Krox 20结合位点介导的直接Krox 20在神经嵴的自我调节的存在。此外，增强子还包括另一个基本元件，其中含有高迁移率族（HMG）盒蛋白的保守结合位点，并对整个神经嵴表达的因子作出反应。与此相一致的NCE强烈激活Sox 10，波峰特异性HMG盒蛋白，在体外与Krox 20的协同作用，和Sox 10的失活阻止Krox 20的表达在迁移的神经嵴的维护。这些结果表明，依赖性的增强子对两个波峰-（Sox 10）和R5-（Krox 20）的具体因素限制其活动的R5-衍生的神经嵴。这种组织也表明了一种机制，从后脑神经上皮细胞的菱形特异性基因表达的转移和维护新兴的神经嵴，可能是更普遍的意义，神经嵴图案。
Neural crest patterning constitutes an important element in the control of the morphogenesis of craniofacial structures. Krox20, a transcription factor gene that plays a critical role in the development of the segmented hindbrain, is expressed in rhombomeres (r) 3 and 5 and in a stream of neural crest cells migrating from r5 toward the third branchial arch. We have investigated the basis of the specific neural crest expression of Krox20 and identified a cis-acting enhancer element (NCE) located 26 kb upstream of the gene that is conserved between mouse, man and chick and can recapitulate the Krox20 neural crest pattern in transgenic mice. Functional dissection of the enhancer revealed the presence of two conserved Krox20 binding sites mediating direct Krox20 autoregulation in the neural crest. In addition, the enhancer included another essential element containing conserved binding sites for high mobility group (HMG) box proteins and which responded to factors expressed throughout the neural crest. Consistent with this the NCE was strongly activated in vitro by Sox10, a crest-specific HMG box protein, in synergism with Krox20, and the inactivation of Sox10 prevented the maintenance of Krox20 expression in the migrating neural crest. These results suggest that the dependency of the enhancer on both crest- (Sox10) and r5- (Krox20) specific factors limits its activity to the r5-derived neural crest. This organisation also suggests a mechanism for the transfer and maintenance of rhombomere-specific gene expression from the hindbrain neuroepithelium to the emerging neural crest and may be of more general significance for neural crest patterning.