Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases.

Bibliographic Collection: 
Publication Type: Journal Article
Authors: Lin, Guan Ning; Corominas, Roser; Lemmens, Irma; Yang, Xinping; Tavernier, Jan; Hill, David E; Vidal, Marc; Sebat, Jonathan; Iakoucheva, Lilia M
Year of Publication: 2015
Journal: Neuron
Volume: 85
Issue: 4
Pagination: 742-54
Date Published: 2015 Feb 18
Publication Language: eng
ISSN: 1097-4199
Keywords: Adolescent, Adult, Aged, 80 and over, Brain, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Cullin Proteins, DNA Copy Number Variations, Fetus, Gene Expression Profiling, Gene Regulatory Networks, Humans, Infant, Infant, Newborn, Mental Disorders, Neuroglia, Neurons, Nuclear Proteins, rhoA GTP-Binding Protein, Signal Transduction, Young Adult

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.

DOI: 10.1016/j.neuron.2015.01.010
Alternate Journal: Neuron