Open AccessAdenomatous Polyposis Coli Is Essential for Both Neuronal Differentiation and Maintenance of Adult Neural Stem Cells in Subventricular Zone and Hippocampus
Author(s) -
Imura Tetsuya,
Wang Xiaohong,
Noda Tetsuo,
Sofroniew Michael V.,
Fushiki Shinji
Publication year - 2010
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.524
Subject(s) - biology , neurogenesis , neuroblast , subventricular zone , neural stem cell , microbiology and biotechnology , rostral migratory stream , glial fibrillary acidic protein , dentate gyrus , adenomatous polyposis coli , stem cell , neurod , conditional gene knockout , neuroepithelial cell , olfactory bulb , cellular differentiation , immunology , neuroscience , hippocampal formation , central nervous system , genetics , colorectal cancer , immunohistochemistry , cancer , gene , phenotype
The tumor suppressor adenomatous polyposis coli (APC) is a multifunctional protein that not only inhibits the Wnt signaling pathway by promoting the degradation of β‐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 β‐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 β‐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