Abstract
The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes (presumptive upper motor neuron (UMN) phenotypes) of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling.
Significance Statement Although the cerebral cortex is organized into functionally unique subdivisions or areas, the areal specification has not been studied extensively in PSC-based neurodevelopmental models. Here, we report a culture system to control the areal identity of PSC-derived cerebral cortical progenitors along the R-C axis by modulating FGF8 signaling. Treatment with FGF8 conferred rostral (the sensorimotor cortex) identity on cerebral cortical progenitors, whereas these progenitors retained caudal (the temporal lobe) identity in the absence of FGF8. By using this culture system, we succeeded in modeling area-specific forebrain phenotypes (presumptive UMN phenotypes) of ALS. This system offers a novel platform in the field of human neurodevelopment and neurologic disease modeling.
Footnotes
H.O. serves as a paid scientific advisor to SanBio Co. Ltd. and K Pharma Inc. The remaining authors declare no competing financial interests.
This study was supported by grants from the New Energy and Industrial Technology Development Organization, the Ministry of Education, Science, Sports and Culture (MEXT) of Japan, and the Ministry of Health, Labour and Welfare (MHLW) of Japan to H.O. and W.A.; by the Program for Intractable Disease Research Utilizing Disease-Specific iPS Cells funded by the Japan Science and Technology Agency (JST)/Japan Agency for Medical Research and Development (AMED) to H.O. and W.A.; by the Practical Research Project for Rare/Intractable Diseases by AMED to H.O and M.A; by the Ice Bucket Challenge Grant from Japan ALS Association to H.O.; and by Keio University Research Grants for Life Science and Medicine to K.I. We are grateful to N. Nakatsuji and H. Suemori (Kyoto University) for ESCs; S. Yamanaka (Kyoto University) for control iPSCs; and all members of the H.O. laboratory for encouragement and kind support.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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