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Neuron. 2015 Feb 18;85(4):742-54. doi: 10.1016/j.neuron.2015.01.010.

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

Author information

1
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
2
Department of Medical Protein Research, VIB, and Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
3
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.
4
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.
5
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: lilyak@ucsd.edu.

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.

PMID:
25695269
PMCID:
PMC4335356
DOI:
10.1016/j.neuron.2015.01.010
[Indexed for MEDLINE]
Free PMC Article

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