The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells.
Neural precursor cells (NPCs) have the ability to self-renew and to give rise to neuronal and glial lineages. The fate decision of NPCs between proliferation and differentiation determines the number of differentiated cells and the size of each region of the brain. However, the signals that regulate the timing of neuronal differentiation remain unclear. Here, we show that Wnt signaling inhibits the self-renewal capacity of mouse cortical NPCs, and instructively promotes their neuronal differentiation. Overexpression of Wnt7a or of a stabilized form of beta-catenin in mouse cortical NPC cultures induced neuronal differentiation even in the presence of Fgf2, a self-renewal-promoting factor in this system. Moreover, blockade of Wnt signaling led to inhibition of neuronal differentiation of cortical NPCs in vitro and in the developing mouse neocortex. Furthermore, the beta-catenin/TCF complex appears to directly regulate the promoter of neurogenin 1, a gene implicated in cortical neuronal differentiation. Importantly, stabilized beta-catenin did not induce neuronal differentiation of cortical NPCs at earlier developmental stages, consistent with previous reports indicating self-renewal-promoting functions of Wnts in early NPCs. These findings may reveal broader and stage-specific physiological roles of Wnt signaling during neural development.
Hirabayashi
Yusuke
Y
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Itoh
Yasuhiro
Y
Tabata
Hidenori
H
Nakajima
Kazunori
K
Akiyama
Tetsu
T
Masuyama
Norihisa
N
Gotoh
Yukiko
Y
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000235:genetics*; D017931:DNA Primers; D005121:Extremities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics*; D051153:Wnt Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; D051176:beta Catenin