Kawai Hiroki, Kawaguchi Daichi, Kuebrich Benjamin D, Kitamoto Takeo, Yamaguchi Masahiro, Gotoh Yukiko, Furutachi Shohei
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan,
J Neurosci. 2017 Dec 6;37(49):11867-11880. doi: 10.1523/JNEUROSCI.0001-17.2017. Epub 2017 Nov 3.
In the adult mammalian brain, neural stem cells (NSCs) generate new neurons throughout the mammal's lifetime. The balance between quiescence and active cell division among NSCs is crucial in producing appropriate numbers of neurons while maintaining the stem cell pool for a long period. The Notch signaling pathway plays a central role in both maintaining quiescent NSCs (qNSCs) and promoting cell division of active NSCs (aNSCs), although no one knows how this pathway regulates these apparently opposite functions. Notch1 has been shown to promote proliferation of aNSCs without affecting qNSCs in the adult mouse subependymal zone (SEZ). In this study, we found that Notch3 is expressed to a higher extent in qNSCs than in aNSCs while Notch1 is preferentially expressed in aNSCs and transit-amplifying progenitors in the adult mouse SEZ. Furthermore, Notch3 is selectively expressed in the lateral and ventral walls of the SEZ. Knockdown of Notch3 in the lateral wall of the adult SEZ increased the division of NSCs. Moreover, deletion of the gene resulted in significant reduction of qNSCs specifically in the lateral and ventral walls, compared with the medial and dorsal walls, of the lateral ventricles. Notch3 deletion also reduced the number of qNSCs activated after antimitotic cytosine β-D-arabinofuranoside (Ara-C) treatment. Importantly, Notch3 deletion preferentially reduced specific subtypes of newborn neurons in the olfactory bulb derived from the lateral walls of the SEZ. These results indicate that Notch isoforms differentially control the quiescent and proliferative steps of adult SEZ NSCs in a domain-specific manner. In the adult mammalian brain, the subependymal zone (SEZ) of the lateral ventricles is the largest neurogenic niche, where neural stem cells (NSCs) generate neurons. In this study, we found that Notch3 plays an important role in the maintenance of quiescent NSCs (qNSCs), while Notch1 has been reported to act as a regulator of actively cycling NSCs. Furthermore, we found that Notch3 is specifically expressed in qNSCs located in the lateral and ventral walls of the lateral ventricles and regulates neuronal production of NSCs in a region-specific manner. Our results indicate that Notch3, by maintaining the quiescence of a subpopulation of NSCs, confers a region-specific heterogeneity among NSCs in the adult SEZ.
在成年哺乳动物大脑中，神经干细胞（NSCs）在哺乳动物的整个生命周期内都能产生新的神经元。神经干细胞静止与活跃细胞分裂之间的平衡对于产生适量的神经元并长期维持干细胞池至关重要。Notch信号通路在维持静止神经干细胞（qNSCs）和促进活跃神经干细胞（aNSCs）的细胞分裂中都起着核心作用，尽管尚无人知晓该通路如何调节这些明显相反的功能。研究表明，Notch1可促进成年小鼠脑室下区（SEZ）中活跃神经干细胞的增殖，而不影响静止神经干细胞。在本研究中，我们发现，在成年小鼠脑室下区，Notch3在静止神经干细胞中的表达程度高于活跃神经干细胞，而Notch1则优先表达于活跃神经干细胞和过渡扩增祖细胞中。此外，Notch3在脑室下区的侧壁和腹侧壁选择性表达。敲低成年脑室下区侧壁中的Notch3可增加神经干细胞的分裂。此外，与侧脑室的内侧壁和背侧壁相比，Notch3基因的缺失导致脑室下区侧壁和腹侧壁中的静止神经干细胞显著减少。Notch3的缺失还减少了抗有丝分裂的β-D-阿拉伯呋喃糖胞苷（Ara-C）处理后被激活的静止神经干细胞数量。重要的是，Notch3的缺失优先减少了源自脑室下区侧壁的嗅球中特定亚型的新生神经元数量。这些结果表明，Notch异构体以区域特异性方式差异控制成年脑室下区神经干细胞的静止和增殖步骤。在成年哺乳动物大脑中，侧脑室的脑室下区是最大的神经发生微环境，神经干细胞在此产生神经元。在本研究中，我们发现Notch3在维持静止神经干细胞中起重要作用，而Notch1据报道是活跃循环神经干细胞的调节因子。此外，我们发现Notch3在位于侧脑室侧壁和腹侧壁的静止神经干细胞中特异性表达，并以区域特异性方式调节神经干细胞的神经元生成。我们的结果表明，Notch3通过维持一部分神经干细胞的静止状态，赋予成年脑室下区神经干细胞区域特异性异质性。
