November 28, 2020

Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism

Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorders, and has significant effect on brain size. We generated cortical organoids to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have "mirror" effects on cell proliferation, neuronal maturation and synapse number, consistent with "mirror" effects on brain development in humans. Excess neuron number along with depletion of neural progenitors in deletions, and "mirror" phenotypes in duplications, demonstrate dosage-dependent impact of 16p11.2 CNV on early neurogenesis. Transcriptomic and proteomic profiling revealed synaptic defects and neuron migration as key drivers of 16p11.2 functional effect. Treatment with the RhoA inhibitor Rhosin rescued neuron migration. We implicate upregulation of small GTPase RhoA as one of the pathways impacted by the 16p11.2 CNV. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development.

 bioRxiv Subject Collection: Neuroscience

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