Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism.

Autor:	Urresti J; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Zhang P; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Moran-Losada P; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Yu NK; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Negraes PD; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Pediatrics/Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA., Trujillo CA; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Pediatrics/Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA., Antaki D; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA., Amar M; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Chau K; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Pramod AB; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Diedrich J; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Tejwani L; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Pediatrics/Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA., Romero S; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Pediatrics/Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA., Sebat J; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.; University of California San Diego, Beyster Center for Psychiatric Genomics, La Jolla, CA, USA., Yates Iii JR; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Muotri AR; Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA. muotri@ucsd.edu.; Department of Pediatrics/Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA. muotri@ucsd.edu.; University of California San Diego, Kavli Institute for Brain and Mind, La Jolla, CA, USA. muotri@ucsd.edu.; Center for Academic Research and Training in Anthropogeny (CARTA), La Jolla, CA, USA. muotri@ucsd.edu., Iakoucheva LM; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. lilyak@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Molecular psychiatry [Mol Psychiatry] 2021 Dec; Vol. 26 (12), pp. 7560-7580. Date of Electronic Publication: 2021 Aug 26.
DOI:	10.1038/s41380-021-01243-6
Abstrakt:	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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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