Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development

Yoon, Sehyoun; Parnell, Euan; Kasherman, Maria; Forrest, Marc P.; Myczek, Kristoffer; Premarathne, Susitha; Vega, M.C.; Piper, Michael; Jolly, Lachlan A.; Wood, Stephen A.; Penzes, Peter

doi:10.1016/j.neuron.2019.11.003

Cited by 40 publications

(50 citation statements)

References 64 publications

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“…Many of these 42 variants were inherited through unaffected mothers, while others arose de novo. We showed that these male USP9X missense variants cause partial, rather than complete loss of USP9X function 7,8,11 . In particular, these mutations disable brain-specific USP9X functions, while leaving other functions, such as those essential for embryonic viability, intact.…”

Section: Introductionmentioning

confidence: 83%

“…Male USP9X variants in the N-terminal regions have been shown to disrupt subsets of USP9X substrate interactions, rather than all 7 . These substrates are, however, critical specifically for the function of neurodevelopmental signalling pathways TGFβ, mTOR, Notch and Wnt 7 , all of which have been shown to be deregulated in the developing brains of mice lacking Usp9x 11,37,[41][42][43] . It was also striking to see that males shared much of the neurological phenotypical features shared in our female cohorts, but almost none of the other congenital features.…”

Section: Discussionmentioning

confidence: 99%

“…Protein structure modelling of the USP9X catalytic domain variants We employed our recently resolved USP9X UCH catalytic domain structural model 7,11 to interrogate the molecular mechanisms underpinning pathogenicity of the five female missense and single amino acid deletion variants found within (Table 1 and Fig. 3).…”

Section: Variant Prediction Algorithms Support Pathogenicity Of Usp9xmentioning

confidence: 99%

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Missense variant contribution to USP9X-female syndrome

et al. 2020

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USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Variant Prediction Algorithms Support Pathogenicity Of Usp9xmentioning

confidence: 99%

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Missense variant contribution to USP9X-female syndrome

et al. 2020

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“…In recent studies, growing evidence has shown that specific neuronal cell types contribute to the mechanisms of behavioral changes in ASD animal models (Tyzio et al, 2014;Bariselli et al, 2016;Zhang Y. et al, 2016;Wang et al, 2017;Guo et al, 2019). Moreover, a considerable number of studies have suggested an association between ASDs and dendritic spine abnormalities involving different stages, such as spine development, maturation, elimination, and pruning (Tang et al, 2014;Yadav et al, 2017;Yoon et al, 2020). Therefore, it is essential to characterize the morphological changes of distinct cell types in the brain circuits of those animal models of disease, which will greatly help us to understand the etiology of ASD, especially dendritic processes and dendritic spines.…”

Section: Introductionmentioning

confidence: 99%

A Whole-Brain Cell-Type-Specific Sparse Neuron Labeling Method and Its Application in a Shank3 Autistic Mouse Model

Chen

Ren

Liu

et al. 2020

Front. Cell. Neurosci.

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Single neurons, as the basic unit of the brain, consist of a cell body and processes, including dendrites and axons. Even neurons of the same type show various subtle process characteristics to fit into the diverse neural circuits. Different cell types of neurons form complicated circuits in the brain. Therefore, detailed neuronal morphology is required to understand normal neuronal function and pathological mechanisms, such as those that occur in autism. Here, we developed a strategy to sparsely label the same type of neurons throughout the whole brain and tested its application in an autistic animal model-Shank3 knockout (KO) mice. To achieve this, we designed an adeno-associated virus (AAV) that expresses Cre recombinase-dependent regular and membrane-targeted enhanced green fluorescent protein (EGFP) under a human synapsin 1 promoter and verified it in several Cre transgenic mice. We could sparsely label the projection neurons in multiple brain areas by retro-ocular injection of the virus into CaMKIIα-Cre mice. Then, we analyzed the morphology of the projection neurons in Shank3 KO mice with this method. We found differential dendritic complexity and dendritic spine changes in projection neurons in Shank3 KO mice crossed with CaMKIIα-Cre mice compared with littermate control mice in the striatum, cortex, and hippocampus. By combining this method with various Cre mouse lines crossed with mouse models of disease, we can screen the morphological traits of distinct types of neurons throughout the whole brain that will help us to understand the exact role of the specific cell types of neurons not only in autism spectrum disorder (ASD) mouse models but also in other psychiatric disorder mouse models.

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“…Interestingly, Usp9x -/Y;Emx1-Cre mice were further showed hyperactive behaviour in two assays, the elevated plus maze and light-dark box tests (Yoon et al, 2020). Future experiments should also examine whether Usp9x -/Y;Emx1-Cre mice model autistic-like traits, reminiscent of USP9X-deficient patients.…”

Section: Discussionmentioning

confidence: 96%

Molecular mechanisms underlying malformations of cortical development

Oishi¹

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Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioural assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. Adult Nfix+/-mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/-mice exhibit behavioural deficits that model intellectual disability. Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit.

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Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development

Cited by 40 publications

References 64 publications

Missense variant contribution to USP9X-female syndrome

Missense variant contribution to USP9X-female syndrome

A Whole-Brain Cell-Type-Specific Sparse Neuron Labeling Method and Its Application in a Shank3 Autistic Mouse Model

Molecular mechanisms underlying malformations of cortical development

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