A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord
A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord
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DOI：
10.1242/dev.105866
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发表时间：
2014-07-01
期刊：
影响因子：
4.6
通讯作者：
Johnson, Jane E.
中科院分区：
文献类型：
--
作者：
Borromeo, Mark D.;Meredith, David M.;Johnson, Jane E.
兴奋性和抑制性神经元的适当平衡对于脊髓背侧体感信息的正常处理至关重要。两个神经基本的螺旋-环-螺旋转录因子（TF），Ascl 1和Ptf 1a，在指定这些神经元有对比的功能。为了了解Ascl 1和Ptf 1a在这一过程中的功能，我们使用ChIP-Seq和RNA-Seq在胚胎小鼠神经管中鉴定了它们的直接转录靶基因。我们发现，Ascl 1和Ptf 1a直接调节不同的同源域TF指定兴奋性或抑制性神经元的命运。此外，Ascl 1直接调节在神经原程序的几个步骤中发挥作用的基因，包括Notch信号传导、神经元分化、轴突引导和突触形成。相比之下，Ptf 1a直接调节抑制性神经元中神经递质机制的编码基因，以及与Ascl 1调节的神经发育不同的其他后期方面。此外，Ptf 1a通过直接抑制Ascl 1的几个靶点来抑制兴奋性神经元的命运。Ascl 1和Ptf 1a结合序列主要富含特定的E-Box基序（CAGCTG）和Sox、Rfx、Pou和同源结构域因子使用的二级基序。Ptf 1a还结合在CAGATG E-box和其辅因子Rbpj的结合基序中独特富集的序列，提供了影响Ptf 1a结合特异性的两个因素。针对Ascl 1和Ptf 1a确定的直接转录靶点提供了对这些DNA结合蛋白如何在神经元发育中发挥作用的分子理解，特别是作为神经元亚型规范所需的同源域TF的关键调节因子。
The proper balance of excitatory and inhibitory neurons is crucial for normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors (TFs), Ascl1 and Ptf1a, have contrasting functions in specifying these neurons. To understand how Ascl1 and Ptf1a function in this process, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a directly regulate distinct homeodomain TFs that specify excitatory or inhibitory neuronal fates. In addition, Ascl1 directly regulates genes with roles in several steps of the neurogenic program, including Notch signaling, neuronal differentiation, axon guidance and synapse formation. By contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Ascl1 and Ptf1a bind sequences primarily enriched for a specific E-Box motif (CAGCTG) and for secondary motifs used by Sox, Rfx, Pou and homeodomain factors. Ptf1a also binds sequences uniquely enriched in the CAGATG E-box and in the binding motif for its co-factor Rbpj, providing two factors that influence the specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding of how these DNA-binding proteins function in neuronal development, particularly as key regulators of homeodomain TFs required for neuronal subtype specification.