Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases

• Published in: Neuron (Cambridge, Mass.) Vol. 85; no. 4; pp. 742 - 754
• Main Authors: Lin, Guan Ning, Corominas, Roser, Lemmens, Irma, Yang, Xinping, Tavernier, Jan, Hill, David E., Vidal, Marc, Sebat, Jonathan, Iakoucheva, Lilia M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.02.2015; Elsevier Limited
• Subjects: Adolescent; Adult; Aged, 80 and over; Autism; Brain; Brain - embryology; Brain - growth & development; Brain - pathology; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; Cullin Proteins - genetics; Cullin Proteins - metabolism; DNA Copy Number Variations - genetics; Experiments; Fetus; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; Humans; Infant; Infant, Newborn; Lasers; Mental Disorders - genetics; Mental Disorders - pathology; Neuroglia - metabolism; Neuroglia - pathology; Neurons - metabolism; Neurons - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteins; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Signal Transduction - genetics; Studies; Young Adult
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.01.010

The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes. •Rare high-risk CNVs for psychiatric disorders have unique spatiotemporal signatures•Dynamic 16p11.2 protein interaction network reveals changes during brain development•The late mid-fetal period is critical for establishing 16p11.2 network connectivity•KCTD13-Cul3-RhoA pathway may be dysregulated by gene-damaging mutations Deletions and duplications of chromosome 16p11.2 confer a high risk for neuropsychiatric diseases. By integrating the physical interactions of 16p11.2 proteins with spatiotemporal gene expression, Lin et al. implicate the KCTD13-Cul3-RhoA pathway as being crucial for controlling brain size and connectivity.