Muroyama Yuko, Saito Tetsuichiro
Department of Developmental Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Development. 2009 Dec;136(23):3889-93. doi: 10.1242/dev.039180.
In the developing neocortex, neural progenitor cells (NPCs) produce projection neurons of the six cortical layers in a temporal order. Over the course of cortical neurogenesis, maintenance of NPCs is essential for the generation of distinct types of neurons at the required time. Notch signaling plays a pivotal role in the maintenance of NPCs by inhibiting neuronal differentiation. Although Hairy and Enhancer-of-split (Hes)-type proteins are central to Notch signaling, it remains unclear whether other essential effectors take part in the pathway. In this study, we identify Nepro, a gene expressed in the developing mouse neocortex at early stages that encodes a 63 kDa protein that has no known structural motif except a nuclear localization signal. Misexpression of Nepro inhibits neuronal differentiation only in the early neocortex. Furthermore, knockdown of Nepro by siRNA causes precocious differentiation of neurons. Expression of Nepro is activated by the constitutively active form of Notch but not by Hes genes. Nepro represses expression of proneural genes without affecting the expression of Hes genes. Finally, we show that the combination of Nepro and Hes maintains NPCs even when Notch signaling is blocked. These results indicate that Nepro is involved in the maintenance of NPCs in the early neocortex downstream of Notch.
在发育中的新皮层中，神经祖细胞（NPCs）按时间顺序产生六层皮质的投射神经元。在皮质神经发生过程中，NPCs的维持对于在所需时间产生不同类型的神经元至关重要。Notch信号通路通过抑制神经元分化在NPCs的维持中起关键作用。尽管毛状和分裂增强子（Hes）型蛋白是Notch信号通路的核心，但尚不清楚是否有其他重要效应器参与该途径。在本研究中，我们鉴定了Nepro，这是一个在发育中的小鼠新皮层早期表达的基因，编码一种63 kDa的蛋白质，除了核定位信号外没有已知的结构基序。Nepro的错误表达仅在新皮层早期抑制神经元分化。此外，通过siRNA敲低Nepro会导致神经元过早分化。Nepro的表达由Notch的组成型激活形式激活，而不是由Hes基因激活。Nepro抑制神经前体基因的表达，而不影响Hes基因的表达。最后，我们表明即使Notch信号通路被阻断，Nepro和Hes的组合也能维持NPCs。这些结果表明Nepro在Notch下游参与新皮层早期NPCs的维持。
