Page 8 - R. Organoid

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Development of mature forebrain organoids by spatially and

temporally controlling neurodevelopmental cues for

schizophrenia modeling

Seoyoung Choi¹, Eunjee Kim¹, Jihye Han¹, JungHo Kong¹, Gwanghwan Lee¹, Minhyuk Park¹, Sanguk Kim¹˙*,

Kunyoo Shin¹˙*

¹Department of Life Sciences, Pohang University of Science and Technology , Pohang 37673, Republic of Korea

The biggest challenge to study human brain is the lack of experimental systems that can precisely represent the

complexity of human brain. Current brain organoid technology is limited in that it fails to recapitulate cell maturation
in late fetal stages of brain development. Here, we generate human forebrain organoids that reproduce structural

and functional maturity of human fetal brain, by spatially and temporally controlling patterning molecules. Firstly,
the pathway activities of Hedgehog and Wnt signaling are pharmacologically increased to expand the neural

progenitor population at the later stage, leading to increased number of functional neurons. Secondly, correct
organization of developing cortex such as accurate positioning of neuronal layers could be finally achieved by

reconstituting brain organoids with tetracycline-inducible, Reelin-expressing cells. Here, we apply our mature
forebrain organoid system to model schizophrenia. Our organoid system revealed that schizophrenia is accompanied

by massive alterations in enhancer activity, which is caused by mutations in pioneering factors. Taken together, our
work shows the effective strategies to develop mature human forebrain organoids, and will provide the strong

foundation to understand various neurological disorders.