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The Basic Domain of ATH5 Mediates Neuron-Specific Promoter Activity during Retina Development

机译:ATH5的基本域在视网膜发育过程中介导神经元特定的启动子活性。

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In the developing retina, the gene encoding the β3 subunit of the neuronal nicotinic receptor, a specific marker of retinal ganglion cells, is under the direct control of the atonal homolog 5 (ATH5) basic helix-loop-helix (bHLH) transcription factor. Although quite short (143 bp in length), the β3 promoter has the remarkable capacity to discriminate between ATH5 and the other neuronal bHLH proteins expressed in the developing nervous system. We have identified three amino acids within the basic domain that confer specificity to the ATH5 protein. These residues do not mediate direct DNA binding but are required for interaction between ATH5 and chromatin-associated proteins during retina development. When misexpressed in neurons, the myogenic bHLH factor MyoD is also able to activate the β3 gene. This, however, is achieved not by binding of the protein to the promoter but by dimerization of MyoD with a partner, a process that depends not on the basic domain but on the HLH domain. By sequestering an E-box-binding protein, MyoD relieves the active repression that blocks the β3 promoter in most neurons. The mechanisms used by bHLH proteins to activate β3 thus highlight how ATH5 is selected by the β3 promoter and coordinates the derepression and transcriptional activation of the β3 gene during the specification of retinal ganglion cells.
机译:在发育中的视网膜中,编码神经元烟碱样受体的β3亚基(视网膜神经节细胞的特定标记)的基因直接受非同源同系物5(ATH5)基本螺旋-环-螺旋(bHLH)转录因子的控制。尽管非常短(长度为143 bp),但β3启动子具有显着的能力来区分ATH5和发育中的神经系统中表达的其他神经元bHLH蛋白。我们已经鉴定出在碱性结构域内赋予ATH5蛋白特异性的三个氨基酸。这些残基不介导直接的DNA结合,但是在视网膜发育过程中ATH5和染色质相关蛋白之间的相互作用是必需的。当在神经元中错误表达时,成肌bHLH因子MyoD也能够激活β3基因。但是,这不是通过蛋白质与启动子的结合而是通过MyoD与伴侣的二聚作用实现的,该过程不依赖于基本域,而依赖于HLH域。通过隔离E-box结合蛋白,MyoD可以缓解大多数神经元中阻止β3启动子的活性抑制。因此,bHLH蛋白激活β3的机制突显了在视网膜神经节细胞形成过程中,β3启动子如何选择ATH5,并协调β3基因的抑制和转录激活。

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