Adenomatous Polyposis Coli Is Essential for Both Neuronal Differentiation and Maintenance of Adult Neural Stem Cells in Subventricular Zone and Hippocampus
Adenomatous Polyposis Coli Is Essential for Both Neuronal Differentiation and Maintenance of Adult Neural Stem Cells in Subventricular Zone and Hippocampus
复制标题
DOI：
10.1002/stem.524
复制
发表时间：
2010-11-01
期刊：
影响因子：
5.2
通讯作者：
Fushiki, Shinji
中科院分区：
文献类型：
--
作者：
Imura, Tetsuya;Wang, Xiaohong;Fushiki, Shinji
肿瘤抑制因子腺瘤性息肉病大肠杆菌（APC）是一种多功能蛋白，不仅通过促进β -连环蛋白的降解抑制Wnt信号通路，而且还控制细胞极性、运动和分裂。APC在成人中枢神经系统中大量表达，但其在成人神经发生中的作用尚不清楚。通过条件删除（或敲除）神经胶质纤维酸性蛋白（GFAP）表达细胞（包括脑室下区和海马齿状回的成体神经干细胞（NSCs））中的APC (APC- cko)，我们发现这些细胞的APC表达是成体神经发生的关键组成部分。APC功能丧失导致表达gmap的nsc衍生新神经元显著减少，导致嗅颗粒细胞层体积减少。APC-CKO小鼠神经发生受损有两种不同的机制。首先，APC在迁移的神经母细胞中高表达，APC的缺失干扰了从表达mash1的瞬时扩增细胞向神经母细胞的分化，并伴随β -连环蛋白的积累。结果，APC-CKO小鼠嗅球中迁移神经母细胞减少，而表达mash1的分裂细胞相互增加。其次，APC的缺失促进了成体生发区的枯竭。功能性NSCs及其后代随着年龄的增长而逐渐耗竭。这些研究结果表明，APC的表达在调节细胞内β -catenin水平和新生细胞的神经元分化以及维持NSCs在成人神经源性生态位中的作用至关重要。干细胞2010；28:2053 - 2064
The tumor suppressor adenomatous polyposis coli (APC) is a multifunctional protein that not only inhibits the Wnt signaling pathway by promoting the degradation of beta-catenin but also controls cell polarity, motility, and division. APC is abundantly expressed in the adult central nervous system, but its role in adult neurogenesis remains unknown. Using conditional deletion (or knockout) of APC (APC-CKO) from glial fibrillary acidic protein (GFAP)-expressing cells including adult neural stem cells (NSCs) in the subventricular zone and hippocampal dentate gyrus, we show that APC expression by these cells is a critical component of adult neurogenesis. Loss of APC function resulted in a marked reduction of GFAP-expressing NSC-derived new neurons, leading to the decreased volume of olfactory granule cell layer. Two distinct mechanisms account for impaired neurogenesis in APC-CKO mice. First, APC was highly expressed in migrating neuroblasts and APC deletion disturbed the differentiation from Mash1-expressing transient amplifying cells to neuroblasts with concomitant accumulation of beta-catenin. As a result, migrating neuroblasts decreased, whereas Mash1-expressing dividing cells reciprocally increased in the olfactory bulb of APC-CKO mice. Second, APC deletion promoted an exhaustion of the adult germinal zone. Functional NSCs and their progeny progressively depleted with age. These findings demonstrate that APC expression plays a key role in regulating intracellular beta-catenin level and neuronal differentiation of newly generated cells, as well as maintaining NSCs in the adult neurogenic niche. STEM CELLS 2010;28:2053-2064