Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20.
Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20.
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发表时间：
1998-02
期刊：
影响因子：
4.6
通讯作者：
T. Theil;M. Frain;P. Gilardi-Hebenstreit;A. Flenniken;P. Charnay;D. Wilkinson
中科院分区：
文献类型：
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作者：
T. Theil;M. Frain;P. Gilardi-Hebenstreit;A. Flenniken;P. Charnay;D. Wilkinson
脊椎动物后脑的分割导致一系列具有不同身份的菱形核(R)的形成。最近的研究已经发现了调控这一过程的转录因子之间的调控联系，但人们对这些调控因子如何与介导细胞-细胞信号传递的分子之间的关系知之甚少。Eph受体酪氨酸激酶基因EphA4(Sek-1)在R3和R5中表达，功能阻断实验表明它参与限制奇数和偶数菱形细胞的混合。我们已经分析了转基因小鼠中EphA4基因的顺式作用调控序列，并确定了一个470bp的增强子元件，它驱动R3和R5的特异性表达。在这个元件中，我们已经确定了KROX-20转录因子的八个结合位点，该转录因子也在R3和R5中表达。这些结合位点的突变取消了R3/R5增强子的活性，KROX-20的异位表达导致增强子的异位激活。这些数据表明KROX-20是EphA4的直接转录激活因子。结合KROX-20调控HOX基因表达的证据，我们的发现揭示了一种机制，通过这种机制，细胞的身份和运动相结合，从而产生了严格限制的节段域。
Segmentation of the vertebrate hindbrain leads to the formation of a series of rhombomeres (r) with distinct identities. Recent studies have uncovered regulatory links between transcription factors governing this process, but little is known of how these relate to molecules mediating cell-cell signalling. The Eph receptor tyrosine kinase gene EphA4 (Sek-1) is expressed in r3 and r5, and function-blocking experiments suggest that it is involved in restricting intermingling of cells between odd- and even-numbered rhombomeres. We have analysed the cis-acting regulatory sequences of the EphA4 gene in transgenic mice and identified a 470 bp enhancer element that drives specific expression in r3 and r5. Within this element, we have identified eight binding sites for the Krox-20 transcription factor that is also expressed in r3 and r5. Mutation of these binding sites abolishes r3/r5 enhancer activity and ectopic expression of Krox-20 leads to ectopic activation of the enhancer. These data indicate that Krox-20 is a direct transcriptional activator of EphA4. Together with evidence that Krox-20 regulates Hox gene expression, our findings reveal a mechanism by which the identity and movement of cells are coupled such that sharply restricted segmental domains are generated.