Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors
Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors
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DOI：
10.1242/dev.01179
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发表时间：
2004-07-01
期刊：
影响因子：
4.6
通讯作者：
Pfaff, SL
中科院分区：
文献类型：
--
作者：
Lee, SK;Jurata, LW;Pfaff, SL
建立指定神经元命运所需的基因表达的适当的空间和时间模式的基础转录机制定义不清。我们已经确定了Hb 9基因在发育中的运动神经元中是如何表达的，以了解转录是如何定向到发育中的CNS中的特定细胞的。我们发现，非特异性的通用激活蛋白，如E2 F和Sp1能够驱动广泛的低水平转录的Hb 9在许多细胞类型的整个神经管，然而，他们的活动是由特定的阻遏物和激活复合物调制。Hb 9的通用激活因子被阻遏蛋白Irx 3和Nkx2.2抑制而不触发不适当的转录。高水平的运动神经元表达是通过在位于-7096至-6896的Hb 9的进化保守的紧凑片段上组装增强子来实现的。与该增强子相互作用的LIM-HD和bHLH蛋白质的集合随着运动神经元发育的进展而改变，从而促进发育和成熟运动神经元中Hb 9表达的激活和维持。这些发现为神经管中基因调控和细胞命运规范的去阻遏模型提供了直接支持，并为增强子在靶向脊髓中单个神经元亚型基因表达中的作用提供了支持。
The underlying transcriptional mechanisms that establish the proper spatial and temporal pattern of gene expression required for specifying neuronal fate are poorly defined. We have characterized how the Hb9 gene is expressed in developing motoneurons in order to understand how transcription is directed to specific cells within the developing CNS. We found that non-specific general-activator proteins such as E2F and Sp1 are capable of driving widespread low level transcription of Hb9 in many cell types throughout the neural tube; however, their activity is modulated by specific repressor and activator complexes. The general-activators of Hb9 are suppressed from triggering inappropriate transcription by repressor proteins Irx3 and Nkx2.2. High level motoneuron expression is achieved by assembling an enhancesome on a compact evolutionarily-conserved segment of Hb9 located from -7096 to -6896. The ensemble of LIM-HD and bHLH proteins that interact with this enhancer change as motoneuron development progresses, facilitating both the activation and maintenance of Hb9 expression in developing and mature motoneurons. These findings provide direct support for the derepression model of gene regulation and cell fate specification in the neural tube, as well as establishing a role for enhancers in targeting gene expression to a single neuronal subtype in the spinal cord.