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Self-Organized Formation of Polarized Cortical Tissues from ESCs and Its Active Manipulation by ExtrinsicSignals
Mototsugu Eiraku1,Kiichi Watanabe1,Mami Matsuo-Takasaki1,Masako Kawada1,Shigenobu Yonemura2,Michiru Matsumura1,Takafumi Wataya1,Ayaka Nishiyama1,Keiko Muguruma1andYoshiki Sasai1,,
1 Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
2 Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
SUMMARY
Here, we demonstrate self-organized formation of apico-basally polarized cortical tissues from ESCs using an efficient three-dimensional aggregation culture (SFEBq culture). The generated cortical neurons are functional, transplantable, and capable of forming proper long-range connections invivo and invitro. The regional identity of the generated pallial tissues can be selectively controlled (into olfactory bulb, rostral and caudal cortices, hem, and choroid plexus) by secreted patterning factors such as Fgf, Wnt, and BMP. In addition, the invivo-mimicking birth order of distinct cortical neurons permits the selective generation of particular layer-specific neurons by timed induction of cell-cycle exit. Importantly, cortical tissues generated from mouse and human ESCs form a self-organized structure that includes four distinct zones (ventricular, early and late cortical-plate, and Cajal-Retzius cell zones) along the apico-basal direction. Thus, spatial and temporal aspects of early corticogenesis are recapitulated and can be manipulated in this ESC culture.