期刊
NATURE
卷 545, 期 7652, 页码 54-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature22330
关键词
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资金
- NIH/National Institute of Mental Health (NIMH) [R01MH100900, R01MH100900-02S1]
- NIMH BRAINS Award [R01MH107800]
- California Institute of Regenerative Medicine (CIRM)
- MQ Fellow Award
- Donald E. and Delia B. Baxter Foundation
- Kwan Research Fund
- Stanford Start-up Funds
- Child Research Health Institute (CHRI)
- Walter V. and Idun Berry Postdoctoral Fellowship
- Stanford Medicine Dean's Fellowship
- American Epilepsy Society
- Wishes for Elliott Foundation
- NIH [5P01HG00020526]
- UCSF Program for Breakthrough Biomedical Research
- Sandler Foundation
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (gamma-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca(V)1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
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