Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling

Richter, Melanie; Murtaza, Nadeem; Scharrenberg, Robin; White, Stuart C.; Johanns, Ole; Walker, Susan; Yuen, Ryan K. C.; Schwanke, Birgit; Bedürftig, Bianca; Henis, Melad; Scharf, Sarah; Kraus, Vanessa; Dörk, Ronja; Hellmann, Jakob; Lindenmaier, Zsuzsa; Ellegood, Jacob; Hartung, Henrike; Kwan, Vickie; Sedlacik, Jan; Fiehler, Jens; Schweizer, Michaela; Lerch, Jason P.; Hanganu‐Opatz, Ileana L.; Morellini, Fabio; Scherer, Stephen W.; Singh, Karun K.; Anda, Froylán Calderón de

doi:10.1038/s41380-018-0025-5

Cited by 143 publications

(222 citation statements)

References 95 publications

(96 reference statements)

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“…Spatial expression profiles taken from the latest RNA-sequencing data from Genotype-Tissue Expression ( GTEx ) version 7 (31) show that TAOK2 is widely expressed in the central nervous system, especially the cerebellum. TAOK2 is part of the neurodevelopment gene set and has been shown to regulate brain size and neural connectivity, and is present in the 16p11.2 microdeletion region, a rare structural variant that has been associated with range of neurodevelopmental phenotypes including autism, ADHD, and intellectual disability (32–36). Deletion of TAOK2 in mice was found to lead to deficits in dendritic growth, synaptic formation, cortical layering, and autism-associated phenotypes (36).…”

Section: Discussionmentioning

confidence: 99%

“…TAOK2 is part of the neurodevelopment gene set and has been shown to regulate brain size and neural connectivity, and is present in the 16p11.2 microdeletion region, a rare structural variant that has been associated with range of neurodevelopmental phenotypes including autism, ADHD, and intellectual disability (32–36). Deletion of TAOK2 in mice was found to lead to deficits in dendritic growth, synaptic formation, cortical layering, and autism-associated phenotypes (36). We postulate that altered regulation of TAOK2 affects brain development and ultimately results in reductions in the size of brain regions seen in ADHD.…”

Section: Discussionmentioning

confidence: 99%

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Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Hess

Radonjić

Patak

et al. 2019

Preprint

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Genetically influenced changes in brain organization occur over the course of development. Large-scale brain imaging studies by the ENIGMA Consortium identified structural changes associated with attention-deficit/hyperactivity disorder (ADHD). It is not clear why some brain regions are impaired and others spared by the etiological risks for ADHD. We hypothesized that spatial variation in brain cell organization and/or pathway expression levels contribute to selective brain region vulnerability (SBRV) in ADHD. In this study, we used the largest available collection of imaging results from the ADHD ENIGMA Consortium along with high-resolution postmortem brain microarray data from Allen Brain Atlas from 22 sub-cortical and cortical brain regions to investigate our selective brain region vulnerability (SBRV) hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and non-neuronal cells in the brain. We then assessed the relationships between gene set expression levels, cell abundance, and standardized effect sizes representing regional changes in brain sizes in cases of ADHD. Our analysis yielded significant correlations between apoptosis, autophagy, and neurodevelopment genes with reductions in regional brain sizes in ADHD, along with associations to regional abundances of dopaminergic neurons, astrocytes, oligodendrocytes, and neural progenitor cells. This works provides novel mechanistic insights into SBRV in ADHD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Hess

Radonjić

Patak

et al. 2019

Preprint

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“…Iyer et al also screened homologs of 16p11.2 genes in Drosophila melaogaster using RNAi knockdown, and found that 10 out of 14 homologs contributed to global developmental defects as well as specific neuronal and cellular defects in the developing fly eye (46). Further, mouse models for 15 genes within the 16p11.2 region have been generated to test for defects in development and neuronal behavior (45,48–50,68–80). For example, Taok2 -/- mice have increased brain size, behavioral defects, and impaired synapse development (50), Kcdt13 +/- mice show defects in hippocampal synaptic transmission and decreased dendritic complexity (45), Mapk3 +/- mice show behavior anomalies, abnormal synapse function and reduced cell proliferation during development (68,69), and Mvp +/- mice show decreased plasticity and synaptic defects in ocular neurons (48) ( Figure 2B ).…”

Section: A Case For a Multi-genic Model Of Cnv Pathogenicitymentioning

confidence: 99%

“…Further, mouse models for 15 genes within the 16p11.2 region have been generated to test for defects in development and neuronal behavior (45,48–50,68–80). For example, Taok2 -/- mice have increased brain size, behavioral defects, and impaired synapse development (50), Kcdt13 +/- mice show defects in hippocampal synaptic transmission and decreased dendritic complexity (45), Mapk3 +/- mice show behavior anomalies, abnormal synapse function and reduced cell proliferation during development (68,69), and Mvp +/- mice show decreased plasticity and synaptic defects in ocular neurons (48) ( Figure 2B ). Importantly, these models of individual genes do not fully recapitulate the phenotypes observed in models of the entire CNV (81–85).…”

Section: A Case For a Multi-genic Model Of Cnv Pathogenicitymentioning

confidence: 99%

An interaction-based model for neuropsychiatric features of copy-number variants

Jensen

Girirajan

2018

Preprint

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18Variably expressive copy-number variants (CNVs) are characterized by extensive phenotypic 19 heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for 20 these phenotypes within each CNV have not been successful. Here, we posit using multiple lines 21 of evidence, including pathogenicity metrics, functional assays of model organisms, and gene 22 expression data, that multiple genes within each CNV region are likely responsible for the 23 observed phenotypes. We propose that candidate genes within each region likely interact with 24 each other through shared pathways to modulate the individual gene phenotypes, emphasizing 25 the genetic complexity of CNV-associated neuropsychiatric features. 26 27 28A case for a multi-genic model of CNV pathogenicity 29 Since the advent of large-scale sequencing studies, the number of genes associated with 30 neurodevelopmental disorders such as autism, intellectual disability, and schizophrenia has 31 increased dramatically. For example, nearly 200 genes have been identified with recurrent de 32 novo mutations in both individuals with autism and intellectual disability (1-8). In fact, complex 33 human disease phenotypes can be influenced by variation in both a small number of core genes 34 with large effect size and a large number of modifier genes with small effect size, accounting for 35 the large number of candidate neurodevelopmental genes (9,10). The application of a multi-genic 36 model for disease pathogenicity has not been fully expanded to cover copy-number variants 37 (CNVs), or large duplications and deletions in the genome. The prevailing notion of single 38 causative genes for CNV disorders is due to the paradigm of gene discoveries for CNVs 39 associated with genetic syndromes in individuals with specific constellations of clinical features, 40 such as Smith-Magenis syndrome (SMS). Although some variability in phenotypic expression 41 has been documented, these disorders usually occur de novo and are characterized by high 42 penetrance for the observed phenotypes (11,12) (Figure 1). In these cases, individuals 43 manifesting the characteristic features of the syndrome but with either atypical breakpoints or 44 mutations in individual genes within the CNV region were used to identify causative genes for 45 the major phenotypes (13-15). These causative genes, such as RAI1 for SMS, were then 46 confirmed by recapitulating conserved phenotypes of the deletion using functional evaluations in 47 animal models (16,17). 48 In contrast, another category of CNVs has been identified in individuals with 49 neurodevelopmental disorders, including duplications and deletions at proximal 16p11.2, 3q29, 50 distal 16p11.2, and 1q21.1 (18-21). Although these CNVs are enriched in affected individuals 51 compared to population controls, they are primarily characterized by variable expressivity of 52 clinical features (12,22-26) (Figure 1B). For example, the 16p11.2 deletion has been implicated 53 in 1% of individuals with idiopathic autism (...

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“…In addition to its control in mRNA translation, mTORC1 has been described as a postsynaptic voltage sensor, controlling the excitability of neurons (7). In addition, RhoA, which recently has been mechanistically connected to autistic-like behaviour (with marked modifications on locomotion and social skills) in mice after the deletion of the TAOK2 gene (8) and an important mediator of protein recycling in mammalian cells, is connected to the activity of the mTORC1 pathway (9). The second complex, mTORC2, has a lower sensitivity to rapamycin and its activation results in increased phosphorylation of Akt at the serine 473 site (10).…”

Section: Introductionmentioning

confidence: 99%

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

Rial

Puighermanal

Valjent

et al. 2019

Preprint

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As an integrator of molecular pathways, mTOR has been associated with diseases including neurodevelopmental, psychiatric and neurodegenerative disorders as autism, schizophrenia, and Huntington’s disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified.Taking advantage of the D1-mTOR KO mice (males), we combined behavioural, biochemical, electrophysiological and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons (dMSNs) and how this would impact on striatal physiology.Our results indicate deep behavioural changes in absence of mTOR in dMSNs such as decreased spontaneous locomotion, impaired social interaction and repetitive behaviour. These were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spines density that were mechanistically independent of protein synthesis but dependent of RhoA activity.These results identify mTOR RhoA signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related mTORopathies.

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Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling

Cited by 143 publications

References 95 publications

Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

An interaction-based model for neuropsychiatric features of copy-number variants

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

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