Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling
Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling
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DOI：
10.1242/dev.066167
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发表时间：
2011-06-15
期刊：
影响因子：
4.6
通讯作者：
Tejedor, Francisco J.
中科院分区：
文献类型：
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作者：
Haemmerle, Barbara;Ulin, Edgar;Tejedor, Francisco J.
神经前体在正确的位置和时间停止分裂并开始其终末分化的决定，是神经系统中细胞多样性产生的关键一步。在这里，我们发现唐氏综合征候选基因（Mnb/Dyrk1a）在脊椎动物中枢神经系统神经上皮的前瞻性神经元中短暂表达。Mnb/Dyrk1a的功能增益（GoF）诱导增殖阻滞。相反，它的功能丧失（LoF）导致过度增殖和细胞死亡。我们发现MNB/DYRK1A是在转录水平上上调细胞周期蛋白依赖性激酶抑制剂p27（KIP1）在胚胎鸡脊髓和小鼠端脑中的表达的必要和充分条件，支持MNB/DYRK1A在脊椎动物中枢神经细胞周期退出中的调节作用。所有这些作用都需要MNB/DYRK1A的激酶活性。我们还观察到MNB/DYRK1A在单个神经元前体中与NOTCH配体Delta1共表达。此外，我们发现MNB/DYRK1A抑制NOTCH信号，抵消NOTCH胞内结构域（NICD）的促增殖作用，刺激Delta1表达，并且是NOTCH信号减少诱导的神经元分化所必需的。然而，尽管Mnb/Dyrk1a GoF导致神经元前体广泛退出细胞周期，但不足以诱导其分化。值得注意的是，瞬时（ON/OFF） Mnb/Dyrk1a GoF有效地诱导了神经元分化。我们提出，MNB/DYRK1A在神经元前体中的瞬时表达作为一个二进制开关，通过上调p27（KIP1）表达和抑制NOTCH信号传导，耦合了增殖的结束和神经元分化的开始。
The decision of a neural precursor to stop dividing and begin its terminal differentiation at the correct place, and at the right time, is a crucial step in the generation of cell diversity in the nervous system. Here, we show that the Down's syndrome candidate gene (Mnb/Dyrk1a) is transiently expressed in prospective neurons of vertebrate CNS neuroepithelia. The gain of function (GoF) of Mnb/Dyrk1a induced proliferation arrest. Conversely, its loss of function (LoF) caused over proliferation and cell death. We found that MNB/DYRK1A is both necessary and sufficient to upregulate, at transcriptional level, the expression of the cyclin-dependent kinase inhibitor p27(KIP1) in the embryonic chick spinal cord and mouse telencephalon, supporting a regulatory role for MNB/DYRK1A in cell cycle exit of vertebrate CNS neurons. All these actions required the kinase activity of MNB/DYRK1A. We also observed that MNB/DYRK1A is co-expressed with the NOTCH ligand Delta1 in single neuronal precursors. Furthermore, we found that MNB/DYRK1A suppressed NOTCH signaling, counteracted the pro-proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling. Nevertheless, although Mnb/Dyrk1a GoF led to extensive withdrawal of neuronal precursors from the cell cycle, it was insufficient to elicit their differentiation. Remarkably, a transient (ON/OFF) Mnb/Dyrk1a GoF efficiently induced neuronal differentiation. We propose that the transient expression of MNB/DYRK1A in neuronal precursors acts as a binary switch, coupling the end of proliferation and the initiation of neuronal differentiation by upregulating p27(KIP1) expression and suppressing NOTCH signaling.