Oscillations in Notch Signaling Regulate Maintenance of Neural Progenitors
Hiromi Shimojo,1 Toshiyuki Ohtsuka,1 and Ryoichiro Kageyama1,
1 Institute for Virus Research, Kyoto University, and Japan Science and Technology Agency, CREST, Kyoto 606-8507, Japan
Corresponding author
Ryoichiro Kageyama
rkageyam@virus.kyoto-u.ac.jp
Summary
Expression of the Notch effector gene Hes1 is required for maintenance of neural progenitors in the embryonic brain, but persistent and high levels of Hes1 expression inhibit proliferation and differentiation of these cells. Here, by using a real-time imaging method, we found that Hes1 expression dynamically oscillates in neural progenitors. Furthermore, sustained overexpression of Hes1 downregulates expression of proneural genes, Notch ligands, and cell cycle regulators, suggesting that their proper expression depends on Hes1 oscillation. Surprisingly, the proneural gene Neurogenin2 (Ngn2) and the Notch ligand Delta-like1 (Dll1) are also expressed in an oscillatory manner by neural progenitors, and inhibition of Notch signaling, a condition known to induce neuronal differentiation, leads to downregulation of Hes1 and sustained upregulation of Ngn2 and Dll1. These results suggest that Hes1 oscillation regulates Ngn2 and Dll1 oscillations, which in turn lead to maintenance of neural progenitors by mutual activation of Notch signaling.
日本研究人员在新一期《神经元》杂志上报告说，他们经动物实验确认，神经干细胞内的蛋白质“Hes1”会在神经干细胞分化成神经细胞时发生有节律的增减，控制这种干细胞分化的时机。
日本京都大学教授影山龙一郎的研究小组，通过分析实验鼠胎儿脑内所含的神经干细胞，发现其中的“Hes1”蛋白质以2小时至3小时为周期反复增减，神经干细胞也随着这种增减不断自我复制，向神经细胞转化。而如果使“Hes1”含量下降并使其几乎不发挥作用，那么神经干细胞就不能分化成神经细胞。
人们期待通过移植神经干细胞在神经疾病领域进行再生治疗，然而神经干细胞在动物体外几乎不增殖，这是目前将这种干细胞用于再生治疗尚待解决的课题。
研究人员表示，以这项成果为基础，找到控制神经干细胞分化节律的方法，就有望在人体外控制用于治疗的神经干细胞的增殖和分化，进而更有效地移植。（来源：新华网 钱铮）
