Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases
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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.
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MAPK and Rho GTPase signaling have been implicated by gene set enrichment analysis of ASD-associated CNVs.
“MAPK (Pinto et al., 2010) and Rho GTPase (Lin et al., 2015) signaling has been implicated by gene set enrichment analysis of CNVs associated with ASD.”
From Getting to the cores of autism (2019) · cites this paper as Lin et al., 2015
Coexpression of genes within ASD CNVs is enriched in the developing cortex.
“Likewise coexpression of genes within ASD CNVs was reported to be enriched in the developing cortex (Lin et al., 2015).”
From Getting to the cores of autism (2019) · cites this paper as Lin et al., 2015
Approaches integrating spatio-temporal transcriptome with gene mutation discoveries have implicated projection neurons in prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and frontal cortex during fetal development in schizophrenia.
“In particular, these approaches have implicated the projection neurons in the prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia (Gulsuner et al., 2013; Kang et al., 2011; Lin et al., 2015; Parikshak et al., 2013; State and Sestan, 2012; Willsey et al., 2013).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Lin et al., 2015
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16p11.2 Copy Number Variations and Neurodevelopmental Disorders
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Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells
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First glimpses of the neurobiology of autism spectrum disorder
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- Authors
- Lin, G. N., Corominas, R., Lemmens, I., Yang, X., Tavernier, J., Hill, D. E., Vidal, M., Sebat, J., & Iakoucheva, L. M.
- Affiliations
- University of California San Diego (US)
- Ghent University (BE)
- Harvard University (US)
- Corresponding author
- Iakoucheva, Lilia M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 85
- Issue
- 4
- Pages
- 742-754
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4335356
- OpenAlex
- W1975911274
- Cited by
- 155
- References
- 69
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 19 · 2022: 10 · 2021: 20 · 2020: 17 · 2019: 17 · 2018: 14 · 2017: 16 · 2016: 12 · 2015: 5
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (U01MH094411, R01MH091350, R21MH104766, R01MH105524)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065288)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- 16p11.2, copy number variation, autism spectrum disorder, schizophrenia, protein-protein interaction network, cortical development, CUL3, RhoA, de novo mutations, brain size, cortical connectivity, layer 4, mental illness
- MeSH terms
- Adolescent, Adult, Aged, 80 and over, Mental Disorders, Brain, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Fetus, Humans, Infant, Infant, Newborn, Neuroglia, Neurons, Nuclear Proteins, Signal Transduction, rhoA GTP-Binding Protein, Gene Expression Profiling, Cullin Proteins, Gene Regulatory Networks, Young Adult, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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