Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP.
Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP.
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DOI：
10.1016/j.neuron.2009.04.025
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发表时间：
2009-06-11
期刊：
影响因子：
16.2
通讯作者：
Lee, Soo-Kyung
中科院分区：
文献类型：
--
作者：
Lee, Seunghee;Lee, Bora;Lee, Jae W.;Lee, Soo-Kyung
细胞外信号和细胞内转录因子共同指导不同神经元的产生。然而，很少有人知道神经祖细胞如何整合这两个线索和编排染色质的变化神经元规格。在这里，我们报告，外源性信号视黄酸（RA）和内在转录因子神经生成素2（Ngn 2）合作触发转录活性染色质在脊髓运动神经元基因在发展过程中。视黄酸受体（RAR）结合Ngn 2，从而被招募到Ngn 2靶向的运动神经元基因。然后，RA促进组蛋白乙酰转移酶CBP向Ngn 2/RAR复合物的募集，显著诱导组蛋白H3/H4-乙酰化。相应地，CBP及其parabolic p300的及时失活导致运动神经元特化和运动轴突投射的严重缺陷，伴随着运动神经元增强子的组蛋白H3-乙酰化的显著降低。我们的研究揭示了外在RA信号和内在转录因子Ngn 2通过其协同活性触发转录活性染色质来合作用于细胞命运规范的机制。
Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralogue p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell-fate specification through their synergistic activity to trigger transcriptionally active chromatin.
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