Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA175113 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Rare genomic gains at 15q11-q13 are observed in 1-2% of individuals with an Autism Spectrum Disorder (ASD). Because many genes are included here and breakpoints vary between cases, the potential contribution of specific genes is unclear. Cytoplasmic FMR1 interacting protein 1 (CYFIP1) is interesting in this regard given the association of smaller overlapping deletions with each of schizophrenia and intellectual disability. Towards an understanding of how increased CYFIP1 dosage might predispose to neurodevelopmental disease we investigated the consequence of overexpression in multiple systems. We show that CYFIP1 mRNA is increased in lymphoblastoid cells and human brain as a function of 15q dosage. Towards mechanisms, we determined that overexpression of CYFIP1 results in cellular abnormalities in SY5Y cells and mouse neuronal progenitors. Identical abnormalities, as well as anomalies in synaptic morphology, were seen after comparing two BAC transgenic strains to controls. Gene expression profiling at embryonic day 15 identified genes differentially expressed between transgenic and control mice and highlighted dysregulation of mTOR signaling. Finally, treatment of mouse neuronal progenitors with an mTOR inhibitor (Rapamycin) rescued morphologic abnormalities resulting from CYFIP1 overexpression. Together, these data are consistent with the notion that normalization of mTOR signaling, emerging as an important point of convergence in the ASDs, may be of clinical utility in genetically selected populations with a variety of neurodevelopmental disorders.
2015-01-01 | GSE40852 | GEO
Project description:In Alzheimer’s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. In addition to compromising canonical BDNF signalling pathways, TrkB-FL cleavage produces an intracellular fragment (TrkB-ICD), which was shown to accumulate in the nucleus and to display tyrosine kinase activity. To dissect the role of TrkB-ICD overexpression from the loss of endogenous signaling throught TrkB-FL, we used lentiviruses to overexpress the TrkB-ICD sequence in cultured primary cortical neurons and performed morphological, electrophysiological and transcriptomics studies. While TrkB-ICD overexpression did not affect cell survival, it caused a significant decrease in the number of dendritic spines, both compared to untransduced and GFP-transduced neurons. Furthermore, TrkB-ICD overexpressing neurons presented a hyperpolarized resting membrane potential and increased frequency of miniature excitatory postsynaptic currents (mEPSCs). Finally, TrkB-ICD overexpression was associated with the upregulation of genes involved in (i) neuronal survival, growth and differentiation; (ii) neuronal cytoarchitecture and spine morphology; (iii) neurodegenerative processes, including AD; and (iv) synaptic transmission and plasticity. Overall, these results show that TrkB-ICD overexpression causes dendritic spine loss, alters excitatory synaptic transmission and causes transcriptome-wide changes, namely in genes coding for proteins involved in synaptic processes.
2024-07-30 | GSE271487 | GEO
Project description:Evidence suggests that impaired synaptic and firing homeostasis represents a driving force of early Alzheimer’s disease (AD) progression. Here, we examine synaptic and sleep homeostasis in a Drosophila model by overexpressing human amyloid precursor protein (APP), whose duplication and mutations cause familial early-onset AD. We find that APP overexpression induces synaptic hyperexcitability. RNA-seq data indicate exaggerated expression of Ca2+ related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IP3R, but not in hyperexcitable mutants caused by TrpA1 or Shal/Kv4. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IP3R) through activating nuclear factor of activated T cells (NFAT). Strikingly, APP overexpression causes defects in both synaptic downscaling and sleep deprivation induced sleep rebound, and both defects could be restored by inhibiting IP3R. Our findings uncover IP3R as a shared signaling molecular in synaptic downscaling and sleep homeostasis, and its dysregulation may lead to synaptic hyperexcitability and AD progression at early stage.
2022-02-18 | GSE196770 | GEO
Project description:<p>Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, partly through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.</p>
2020-11-03 | MTBLS1952 | MetaboLights
Project description:Regulation of hepatocyte proliferation and liver morphology is of critical importance to tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here we describe a novel role for the ubiquitin ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway. The Hippo pathway has been implicated in control of liver morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease. tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here we describe a novel role for the ubiquitin ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway. The Hippo pathway has been implicated in control of liver morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease.
2022-02-28 | GSE196012 | GEO
Project description:Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the mechanisms underlying Caspr2 function in the central nervous system remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Loss of Caspr2 impairs Purkinje cell dendritic development, alters cell signaling and results in motor coordination deficits. Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomic approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain (ECD) in the molecular layer (ML) of the developing cerebellum. The interaction of Caspr2 ECD with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum, and advances our understanding of how Caspr2 dysfunction might lead to specific brain disorders.
2020-07-13 | PXD018972 | Pride
Project description:This model is based on:
Dynamic modeling of signal transduction by mTOR complexes in cancer
Author:
Mohammadreza Dorvash, Mohammad Farahmandnia, Pouria Mosaddeghi, Mitra Farahmandnejad, Hosein Saber, Mohammadhossein Khorraminejad-Shirazi, Amir Azadi, Iman Tavassoly
Abstract:
Signal integration has a crucial role in the cell fate decision and dysregulation of the cellular signaling pathways is a primary characteristic of cancer. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels, including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein (Le Chatelier’s principle). 2-Components like Phosphatidic Acid (PA) further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes in the cancer cells, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier’s principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. This model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.
2024-09-02 | BIOMD0000000822 | BioModels
Project description:Neurodevelopmental disorders (NDDs) are often associated with mutations that disrupt synaptic function and neuronal differentiation, but the mechanisms linking these genetic alterations to cellular phenotypes remain elusive. Here, we investigate the role of Neurabin I (PPP1R9A), a scaffolding protein critical for synaptic plasticity, in human neurons derived from induced pluripotent stem cells (iPSCs) with CRISPR/Cas9-mediated heterozygous mutation (Neurabin I+/-). We observed that, although mutant neurons exhibit dense and elongated neuritic extensions, they fail to form connections and display disrupted action potentials, as observed in electrophysiological studies. Employing a multi-omics approach that integrates long-read transcriptomics, including single-cell and bulk RNA sequencing, and proteomics, we revealed profound transcriptional, structural, and functional deficits associated with Neurabin I haploinsufficiency. We observed that Neurabin I+/- iNeurons revealed downregulation of key neurogenesis genes and ion channel components, while pathway enrichment highlighted dysregulation in synaptic signaling and axon guidance. Long-read sequencing provided isoform-specific insights, revealing altered expression of Neurabin I isoforms, particularly in cortical excitatory neuron subtypes, implicating isoform-specific regulatory mechanisms in the pathophysiology of NDDs. Proteomic profiling identified differentially expressed proteins enriched in pathways related to synaptic vesicle cycle, neurotransmitter release, and neurodegeneration, further substantiating the functional impact of Neurabin I deficiency. Furthermore, single-cell RNA sequencing delineated distinct neuronal differentiation trajectories, showing that Neurabin I+/- neurons exhibit stalled progression and accumulate in intermediate states, suggesting impaired maturation. Gene-based molecular rescue experiments using Neurabin I overexpression (OE) and antisense oligonucleotides (ASO) partially restored neuronal morphology, transcriptomic profiles, and synaptic protein expression, demonstrating the therapeutic potential of targeting Neurabin I in NDDs. This comprehensive multi-omics study elucidates the critical role of Neurabin I in neuronal differentiation and synaptic function, providing a mechanistic link between Neurabin I mutations and neurodevelopmental pathologies, with implications for therapeutic intervention.
2024-12-06 | GSE283629 | GEO
Project description:In summary, we revealed that maternal DBP exposure activated astrocytes through the AKT/NF-κB/IL-6/JAK2/STAT3 signaling pathway and up-regulated the expression of TSP1, which then affected the density and morphology of dendritic spines and synaptic formation of hippocampal neurons, ultimately leading to decreased autonomy and exploration behavior of offspring.
2023-11-11 | GSE188707 | GEO