RT Journal Article
SR Electronic
T1 Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.25.172262
DO 10.1101/2020.06.25.172262
A1 Jorge Urresti
A1 Pan Zhang
A1 Patricia Moran-Losada
A1 Nam-Kyung Yu
A1 Priscilla D. Negraes
A1 Cleber A. Trujillo
A1 Danny Antaki
A1 Megha Amar
A1 Kevin Chau
A1 Akula Bala Pramod
A1 Jolene Diedrich
A1 Leon Tejwani
A1 Sarah Romero
A1 Jonathan Sebat
A1 John R. Yates III
A1 Alysson R. Muotri
A1 Lilia M. Iakoucheva
YR 2020
UL http://biorxiv.org/content/early/2020/06/27/2020.06.25.172262.abstract
AB 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.Competing Interest StatementDr. Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis, focusing on therapeutic applications customized for autism spectrum disorders and other neurological disorders origin genetics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.