Assembly of functionally integrated human forebrain spheroids | |
Article | |
关键词: PLURIPOTENT STEM-CELLS; INTERNEURON MIGRATION; GENE-EXPRESSION; IN-VITRO; NEURONS; DYSFUNCTION; PROGENITOR; INHIBITION; ASTROCYTES; MATURATION; | |
DOI : 10.1038/nature22330 | |
来源: SCIE |
【 摘 要 】
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.
【 授权许可】
Free