MECP2 duplication and mutations impair NSCs differentiation via miR-197 regulated ADAM10

AbstractHow MECP2 (Methyl-CpG-binding protein 2) duplication affects cortex development remains elusive. We found that elevated MeCP2 expression promotes neurogenesis during cortex development in Tg(MECP2) mouse brain. Ectopic expression of MeCP2 in NPCs inhibits ADAM10 and hence compromises the NOTCH pathway during NPC differentiation. MeCP2 up-regulates miR-197 to down-regulate ADAM10. The enhanced NPC differentiation/migration in Tg(MECP2) embryonic brain can be repressed by overexpression of ADAM10 or a miR-197 inhibitor.Consistently, the reduced neurogenesis induced by three rare MeCP2 missense mutations (H371R, E394K, G428S) identified in a Han Chinese autism spectrum disorders (ASD) cohort, can be reversed by miR-197 both in vitro and in vivo. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for neurogenesis, which is affected by both MeCP2 duplication and mutation.

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Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish

Genes ◽

10.3390/genes11111376 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1376

Author(s):

Alba Pensado-López ◽

Sara Veiga-Rúa ◽

Ángel Carracedo ◽

Catarina Allegue ◽

Laura Sánchez

Keyword(s):

Autism Spectrum Disorders ◽

Autism Spectrum ◽

Experimental Models ◽

Repetitive Behaviors ◽

Restricted Interests ◽

Complex Disorder ◽

Spectrum Disorders ◽

Associated Risk Factors

Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.

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Neurobiology of Autism Spectrum Disorders

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.199 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S45-S46

Author(s):

T.M. Sheldrick-Michel ◽

B.T. Morten ◽

B. Niels ◽

I. Mirolyuba

Keyword(s):

Autism Spectrum Disorders ◽

High Throughput Screening ◽

Drug Testing ◽

Developmental Stages ◽

Disease Model ◽

Behavioral Flexibility ◽

Autism Spectrum ◽

Spectrum Disorders

Autism Spectrum Disorders (ASD) is a group of neurodevelopmental disorders with heterogeneous etiology characterized by deficits in social cognition, communication, and behavioral flexibility. Disturbances on molecular and cellular level in early brain development incl. intercellular communication, an unbalanced ratio between certain neuronal populations and maturation/differentiation process, oxidative stress, happening in embryonal stages, might be promising candidates to explain the development of autistic symptoms.In order to get a deeper understanding of these processes, valid “disease models” are pivotal. A new cutting edge technique, named brain organoids, has been highlighted as a promising candidate for obtaining a better “disease model”.Brain organoids derived from patients induced pluripotent stem cells (iPSC) follow in vivo timeline development; they also have the ability to recreate the right complexity of the brains, developmental stages. On the cellular and gene expression level, organoids demonstrate a high similarity to the developing brain in vivo and can therefore recapitulate early stages of the neurogenesis. To date organoids are the most relevant cellular in vitro platform for the understanding of the mechanisms behind ADS pathology. Investigations of “mini brains” at different time points in their development will give a wider and more detailed picture of the disease dynamic and thus the development of therapeutic and prevention strategies. It is a tool that can be used for effective high throughput screening of chemical compounds as potential drugs (“in sphero” drug testing). Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors declare that they have no competing interest.

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Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders

Translational Psychiatry ◽

10.1038/s41398-021-01525-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jason L. He ◽

Georg Oeltzschner ◽

Mark Mikkelsen ◽

Alyssa Deronda ◽

Ashley D. Harris ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Strong Support ◽

Empirical Support ◽

Brain Regions ◽

Autism Spectrum ◽

Resonance Spectroscopy ◽

Primary Sensorimotor Cortex ◽

Spectrum Disorders ◽

Inhibitory Signaling

AbstractIndividuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

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NBS1 interacts with Notch signaling in neuronal homeostasis

Nucleic Acids Research ◽

10.1093/nar/gkaa716 ◽

2020 ◽

Vol 48 (19) ◽

pp. 10924-10939

Author(s):

Zhong-Wei Zhou ◽

Murat Kirtay ◽

Nadine Schneble ◽

George Yakoub ◽

Mingmei Ding ◽

...

Keyword(s):

Notch Signaling ◽

Notch Pathway ◽

Direct Consequence ◽

Nijmegen Breakage Syndrome ◽

Neuron Development ◽

Genetic Ablation ◽

Notch Activity ◽

And Migration

Abstract NBS1 is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. Mutations in NBS1 cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), of which neuronal deficits, including microcephaly and intellectual disability, are classical hallmarks. Given its function in the DDR to ensure proper proliferation and prevent death of replicating cells, NBS1 is essential for life. Here we show that, unexpectedly, Nbs1 deletion is dispensable for postmitotic neurons, but compromises their arborization and migration due to dysregulated Notch signaling. We find that Nbs1 interacts with NICD-RBPJ, the effector of Notch signaling, and inhibits Notch activity. Genetic ablation or pharmaceutical inhibition of Notch signaling rescues the maturation and migration defects of Nbs1-deficient neurons in vitro and in vivo. Upregulation of Notch by Nbs1 deletion is independent of the key DDR downstream effector p53 and inactivation of each MRN component produces a different pattern of Notch activity and distinct neuronal defects. These data indicate that neuronal defects and aberrant Notch activity in Nbs1-deficient cells are unlikely to be a direct consequence of loss of MRN-mediated DDR function. This study discloses a novel function of NBS1 in crosstalk with the Notch pathway in neuron development.

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Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514657112 ◽

2015 ◽

Vol 112 (48) ◽

pp. 14805-14810 ◽

Cited By ~ 27

Author(s):

Thuy N. Vien ◽

Amit Modgil ◽

Armen M. Abramian ◽

Rachel Jurd ◽

Joshua Walker ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Fragile X ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Membrane Stability ◽

Receptor Subtypes ◽

Neuronal Inhibition ◽

Spectrum Disorders ◽

Spine Structure

Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.

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MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway

Cell Death and Differentiation ◽

10.1038/cdd.2016.152 ◽

2017 ◽

Vol 24 (8) ◽

pp. 1431-1442 ◽

Cited By ~ 20

Author(s):

Xiaoyun Chen ◽

Wei Xiao ◽

Weirong Chen ◽

Xialin Liu ◽

Mingxing Wu ◽

...

Keyword(s):

Epithelial Cells ◽

Notch Signaling ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Notch Pathway ◽

Lens Epithelial Cells ◽

Mesenchymal Transition ◽

Fibrotic Diseases

Abstract Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

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Notch pathway activation targets AML-initiating cell homeostasis and differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20121484 ◽

2013 ◽

Vol 210 (2) ◽

pp. 301-319 ◽

Cited By ~ 94

Author(s):

Camille Lobry ◽

Panagiotis Ntziachristos ◽

Delphine Ndiaye-Lobry ◽

Philmo Oh ◽

Luisa Cimmino ◽

...

Keyword(s):

Tumor Suppressor ◽

Notch Signaling ◽

Myeloproliferative Neoplasms ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Notch Receptor ◽

Pathway Activation ◽

Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

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Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

10.21203/rs.3.rs-34246/v2 ◽

2020 ◽

Author(s):

Wahafu Alafate ◽

Dongze Xu ◽

Wei Wu ◽

Jianyang Xiang ◽

Xudong Ma ◽

...

Keyword(s):

Notch Signaling ◽

Acquired Resistance ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Gene Expression Omnibus ◽

Primary Brain Tumor ◽

Biological Behavior ◽

Clinical Samples

Abstract BackgroundGlioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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Structural and functional analysis of the repressor complex in the Notch signaling pathway ofDrosophila melanogaster

Molecular Biology of the Cell ◽

10.1091/mbc.e11-05-0420 ◽

2011 ◽

Vol 22 (17) ◽

pp. 3242-3252 ◽

Cited By ~ 31

Author(s):

Dieter Maier ◽

Patricia Kurth ◽

Adriana Schulz ◽

Andrew Russell ◽

Zhenyu Yuan ◽

...

Keyword(s):

Cell Culture ◽

Notch Signaling ◽

Target Genes ◽

Notch Pathway ◽

Structural Similarity ◽

Receptor Activation ◽

Notch Signaling Pathway ◽

Repressor Complex

In metazoans, the highly conserved Notch pathway drives cellular specification. On receptor activation, the intracellular domain of Notch assembles a transcriptional activator complex that includes the DNA-binding protein CSL, a composite of human C-promoter binding factor 1, Suppressor of Hairless of Drosophila melanogaster [Su(H)], and lin-12 and Glp-1 phenotype of Caenorhabditis elegans. In the absence of ligand, CSL represses Notch target genes. However, despite the structural similarity of CSL orthologues, repression appears largely diverse between organisms. Here we analyze the Notch repressor complex in Drosophila, consisting of the fly CSL protein, Su(H), and the corepressor Hairless, which recruits general repressor proteins. We show that the C-terminal domain of Su(H) is necessary and sufficient for forming a high-affinity complex with Hairless. Mutations in Su(H) that affect interactions with Notch and Mastermind have no effect on Hairless binding. Nonetheless, we demonstrate that Notch and Hairless compete for CSL in vitro and in cell culture. In addition, we identify a site in Hairless that is crucial for binding Su(H) and subsequently show that this Hairless mutant is strongly impaired, failing to properly assemble the repressor complex in vivo. Finally, we demonstrate Hairless-mediated inhibition of Notch signaling in a cell culture assay, which hints at a potentially similar repression mechanism in mammals that might be exploited for therapeutic purposes.

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Exosomes derived miR-454-3P to promote the progression of colorectal cancer via MIER1-mediated Notch signaling activation.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15108 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15108-e15108

Author(s):

Dawei Li ◽

Senglin Zhao ◽

Ye Xu ◽

Xinxiang Li ◽

Sanjun Cai

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Ectopic Expression ◽

Notch Pathway ◽

Early Response ◽

Mesoderm Induction ◽

Cancer Proliferation ◽

Mesenchymal Transition ◽

Mechanistic Investigation

e15108 Background: Mesoderm induction early response 1 (MIER1) was downregulated and predicted poor prognosis in CRC patients. However, the mechanisms of the down regulation of MIER1 in CRC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors.Here, we identified exosomes derived miR-454-3p as a novel regulator of MIER1 in CRC. Methods: The effect of miR-454-3p expression on cancer proliferation and metastasis was assessed in cells by altering the expression of miR-454-3p in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: Functionally, ectopic expression or silencing of exosomes derived miR-454-3P, respectively, promoted or inhibited CRC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of CRC cells and epithelial to mesenchymal transition of CRC cells in vitro and in vivo. Molecularly, exosomes derived miR-454-3P functioned as an onco-miRNA by activating the MIER1-regulated NOTCH pathway. Overexpression or silencing of MIER1 could partially reverse the effects of the overexpression or repression of exosomes derived miR-454-3P on CRC progress caused by activation of the NOTCH pathway in vitro and in vivo. Clinically, high miR-454-3P expression predicted poor survival in CRC patients, especially combined with low MIER1 expression. Conclusions: Collectively, we identified exosomes derived miR- 454-3p as an onco-miRNA, which acts by directly repressing MIER1 in CRC.

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