title: Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Guan Ning
authors.initials: GN
authors.lastname: Lin
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Roser
authors.initials: R
authors.lastname: Corominas
authors.affiliation: Department of Medical Protein Research, VIB, and Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors.forename: Irma
authors.initials: I
authors.lastname: Lemmens
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medical Protein Research, VIB, and Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: lilyak@ucsd.edu.
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics*; D005333:Fetus; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D001523:Mental Disorders / Q000235:genetics* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D055815:Young Adult; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; C439978:KCTD13 protein, human; D009687:Nuclear Proteins; D020742:rhoA GTP-Binding Protein