Homeodomain transcription factor Phox2a, via cyclic AMP-mediated activation, induces P27Kip1 transcription, coordinating neural progenitor cell cycle exit and differentiation
Homeodomain transcription factor Phox2a, via cyclic AMP-mediated activation, induces P27Kip1 transcription, coordinating neural progenitor cell cycle exit and differentiation
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DOI：
10.1128/mcb.00575-06
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Andrisani, Ourania M.
中科院分区：
文献类型：
--
作者：
Paris, Maryline;Wang, Wen-Horng;Andrisani, Ourania M.
协调神经祖细胞周期退出和分化的机制尚不完全清楚。细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）是转录诱导的，将特定的神经祖细胞从增殖转换为分化。然而，神经元分化特异性转录因子介导的p27（Kip 1）转录尚未确定。我们证明了同源域转录因子Phox 2a，中枢神经系统（CNS）和神经嵴（NC）衍生的去甲肾上腺素能神经元分化所需的，协调细胞周期退出和分化诱导p27（Kip 1）转录。CNS衍生的CAD细胞系和原代NC细胞中的Phox 2a转录和活化由组合的环AMP（cAMP）和骨形态发生蛋白2（BMP 2）信号传导介导。在CAD细胞模型中，cAMP和BMP 2信号最初诱导未分化前体的增殖，随后是p27（Kip 1）转录、G、停滞和神经元分化。Phox 2a或p27（Kip 1）的小干扰RNA沉默抑制p27（Kip 1）转录和神经元分化，表明p27（Kip 1）表达和分化之间的因果关系。相反，通过Tet-off表达系统的异位Phox 2a表达仅在cAMP信号传导存在下促进CAD细胞神经元分化和p27（Kip 1）转录的加速。重要的是，内源性或异位表达的Phox 2a激活cAMP信号结合同源结构域顺式作用元件的p27（Kip 1）启动子在体内和介导CAD和NC细胞中的p27（Kip 1）-荧光素酶表达。我们得出的结论是，cAMP信号传导的发育线索将Phox 2a激活与P27（Kip 1）转录因果联系起来，从而协调神经祖细胞周期退出和分化。
Mechanisms coordinating neural progenitor cell cycle exit and differentiation are incompletely understood. The cyclin-dependent kinase inhibitor p27(Kip1) is transcriptionally induced, switching specific neural progenitors from proliferation to differentiation. However, neuronal differentiation-specific transcription factors mediating p27(Kip1) transcription have not been identified. We demonstrate the homeodomain transcription factor Phox2a, required for central nervous system (CNS)- and neural crest (NC)-derived noradrenergic neuron differentiation, coordinates cell cycle exit and differentiation by inducing p27(Kip1) transcription. Phox2a transcription and activation in the CNS-derived CAD cell line and primary NC cells is mediated by combined cyclic AMP (cAMP) and bone morphogenetic protein 2 (BMP2) signaling. In the CAD cellular model, cAMP and BMP2 signaling initially induces proliferation of the undifferentiated precursors, followed by p27(Kip1) transcription, G, arrest, and neuronal differentiation. Small interfering RNA silencing of either Phox2a or p27(Kip1) suppresses p27(Kip1) transcription and neuronal differentiation, suggesting a causal link between p27(Kip1) expression and differentiation. Conversely, ectopic Phox2a expression via the Tet-off expression system promotes accelerated CAD cell neuronal differentiation and p27(Kip1) transcription only in the presence of cAMP signaling. Importantly, endogenous or ectopically expressed Phox2a activated by cAMP signaling binds homeodomain cis-acting elements of the p27(Kip1) promoter in vivo and mediates p27(Kip1)-luciferase expression in CAD and NC cells. We conclude that developmental cues of cAMP signaling causally link Phox2a activation with P27(Kip1) transcription, thereby coordinating neural progenitor cell cycle exit and differentiation.