期刊
MOLECULAR PSYCHIATRY
卷 26, 期 12, 页码 7560-7580出版社
SPRINGERNATURE
DOI: 10.1038/s41380-021-01243-6
关键词
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资金
- Simons Foundation for Autism Research [345469]
- National Institute of Mental Health [MH109885, MH108528, MH105524, MH104766, MH100175, MH119746]
- UC San Diego IGM Genomics Center, University of California San Diego [P30CA023100]
- UCSD School of Medicine Microscopy Shared Facility [NS047101]
Reciprocal deletion and duplication of the 16p11.2 region are associated with autism spectrum disorders and impact neurodevelopmental processes. CNV dosage affects neuronal maturation, proliferation, and the ratio of neurons to neural progenitors in organoids. Dysregulation of multiple pathways, including neuron migration and actin cytoskeleton, is observed in 16p11.2 CNV, with increased levels of active RhoA implicated in migration deficits.
Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.
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