Reasons for autism investigated in minibrains
2022
Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria(1)
IRCCS, Milan, Italy(2)
IRCCS, Milan, Italy(2)
Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a common cause of autism spectrum disorders (ASD). While the phenotypic spectrum often includes macrocephaly, suggestive of cortical abnormalities, it is unclear how CHD8 haploinsufficiency affects neurodevelopment. Examination of human cerebral organoids has revealed that CHD8 haploinsufficiency disrupts neurodevelopmental pathways with an accelerated and delayed formation of inhibitory and excitatory neurons, respectively, resulting in symmetrically opposite expansions of their proportions at 60 and 120 days. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patient macrocephaly. An isogenic design of patient-specific mutations and mosaic organoids defined genotype-phenotype relationships and revealed their cell-autonomous nature. The results define cell type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell type-specific effects of CHD8 mutations, the study uncovers reproducible developmental changes that can be used to model neurodegenerative diseases.
CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories
Gaia Novarino(1), Giuseppe Testa(2)
Added on: 04-20-2022
[1] https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00363-1#relatedArticles
