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

Lin, Guan Ning; Corominas, Roser; Lemmens, Irma; Yang, Xinping; Tavernier, Jan; Hill, David E.; Vidal, Marc; Sebat, Jonathan; Iakoucheva, Lilia M.

doi:10.1016/j.neuron.2015.01.010

Cited by 150 publications

(180 citation statements)

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“…These data suggest a model wherein KCTD13, probably in coordination with the E3 ubiquitin ligase CUL3 (refs 9, 15, 29), regulates levels of RhoA in post-mitotic neurons to modulate synaptic transmission (Extended Data Fig. 2e).…”

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confidence: 75%

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Kctd13 deletion reduces synaptic transmission via increased RhoA

Escamilla

Filonova

Walker

et al. 2017

Nature

136

171

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Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders1–6 and are among the most prevalent in autism spectrum disorders1,2,7. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes8,9. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study8, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.

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confidence: 75%

“…Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes 8,9 . The function of KCTD13 in the mammalian brain, however, remains unknown.…”

mentioning

confidence: 99%

Kctd13 deletion reduces synaptic transmission via increased RhoA

Escamilla

Filonova

Walker

et al. 2017

Nature

136

171

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“…Causal etiological mechanisms may be overlapping or distinct from our findings. For example, a network analysis study that found that dysregulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate may be a potential determinant of 16p11.2 CNV brain size and connectivity phenotypes (46). Another important point to make is that networks that control dendrites may be similar, overlapping, or different from networks controlling other phenotypes, such as head size.…”

Section: Discussionmentioning

confidence: 99%

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Blizinsky

Díaz-Castro

Forrest

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein-protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.T he architecture of the dendritic arbors defines a pyramidal neuron's dendritic receptive field (1). Moreover, patterns of dendritic arborization are essential to the computational ability of the neuron (1). Generating and maintaining proper dendritic receptive fields is therefore crucial for neural circuit function that underlies complex behaviors. Conversely, alterations in dendrites occur in psychiatric disorders, including schizophrenia and autism spectrum disorder (ASD) (2).Psychiatric disorders have complex genetic architecture that is partly explained by rare variants with high penetrance (3, 4). Though incidences of these rare mutations are low (4-7), the accrued burden of rare variants on disease risk may account for a significant proportion of cases in linked disorders (8). The most well-characterized forms of rare variations are large genomic regional duplications or deletions known as copy number variations (CNVs). CNVs represent large genomic alterations, often encompassing multiple genes, which confer significant risk (odds ratio = 3-30) (9). The increased rare CNV burden is associated with numerous neurodevelopmental psychiatric conditions, including schizophrenia, ASD, and intellectual disability (5, 7, 10, 11). However, due to the large number of genes within CNVs, understanding the relationship between genotype and phenotypes and the rational identification of potential targets for reversing pathologically relevant phenotypes in CNV disorders has been challenging.Recently, much attention has been paid to recurrent microduplication or deletion at the 16p11.2 locus. The ∼600-kb 16p11.2 CNV region encompasses 29 known protein-coding genes and is a hot spot for chromosomal rearrangement (3); 16p11.2 CNVs have been linked to multiple disorders and phenotypes; CNVs of this region are associa...

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“…Rac1 is also downregulated in patients with major depressive disorder and in mice subjected to chronic social defeat, resulting in depression-related behaviors and abnormal spine remodeling [17]. Dysregulated RhoA signaling is likewise implicated in neurodevelopmental disorders associated with autism [18, 19]. Although precise spatiotemporal regulation of Rho-GTPase signaling is necessary for formation and maintenance of functional synapses, little is known about how this is achieved.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses

Duman

Mulherkar

et al. 2015

Neuroscience Letters

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Synapses mediate information flow between neurons and undergo plastic changes in response to experience, which is critical for learning and memory. Conversely, synaptic defects impair information processing and underlie many brain pathologies. Rho-family GTPases control synaptogenesis by transducing signals from extracellular stimuli to the cytoskeleton and nucleus. The Rho-GTPases Rac1 and Cdc42 promote synapse development and the growth of axons and dendrites, while RhoA antagonizes these processes. Despite its significance, many aspects of Rho-GTPase signaling remain relatively unknown. Rho-GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). Though the number of both GEFs and GAPs greatly exceeds that of Rho-GTPases, loss of even a single GEF or GAP often has profound effects on cognition and behavior. Here, we explore how the actions of specific GEFs and GAPs give rise to the precise spatiotemporal activation patterns of Rho-GTPases in neurons. We consider the effects of coupling GEFs and GAPs targeting the same Rho-GTPase and the modular pathways that connect specific cellular stimuli with a given Rho-GTPase via different GEFs. We discuss how the creation of sharp borders between Rho-GTPase activation zones is achieved by pairing a GEF for one Rho-GTPase with a GAP for another and the extensive crosstalk between different Rho-GTPases. Given the importance of synapses for cognition and the fundamental roles that Rho-GTPases play in regulating them, a detailed understanding of Rho-GTPase signaling is essential to the progress of neuroscience.

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

Cited by 150 publications

References 64 publications

Kctd13 deletion reduces synaptic transmission via increased RhoA

Kctd13 deletion reduces synaptic transmission via increased RhoA

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses

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