scholarly journals Impaired KDM2B-mediated PRC1 recruitment to chromatin causes neural stem cell senescence and ASD/ID-like behavioral deficits

2021 ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B Aljazi ◽  
Adam J Moeser ◽  
George I Mias ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Behavioral Deficits ◽  
Adult Mice ◽  
Cycle Arrest ◽  
Developing Mouse Brain ◽  
Underlying Mechanisms ◽  
Polycomb Repressive Complex 1

AbstractAutism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various genetic mutations. Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with human ASD/ID. However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID pathogenesis remain undetermined. Here we show Kdm2b, one of the genes located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the developing mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell cycle arrest, NSC premature senescence, and leading to the loss of NSC populations in the brain. Importantly, the Kdm2b mutation is sufficient to induce ASD/ID-like social and memory deficits in adult mice. Thus, our study reveals a critical role of an epigenetic factor KDM2B in normal brain development, a causality between the Kdm2b mutation and genesis of ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation and NSC senescence to the12q24.31 microdeletion-associated ASD/ID.

scholarly journals Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B. Aljazi ◽  
Yan Wu ◽  
Adam J. Moeser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Critical Function ◽  
Developmental Defects ◽  
Neurodevelopmental Disease ◽  
Developing Mouse Brain

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

scholarly journals LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

2020 ◽  
Vol 12 (565) ◽  
pp. eaay0399
Author(s):  
Changyoun Kim ◽  
Alexandria Beilina ◽  
Nathan Smith ◽  
Yan Li ◽  
Minhyung Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Activated T Cells ◽  
Behavioral Deficits ◽  
Downstream Signaling ◽  
Toll Like Receptor 2 ◽  
Factor Α

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein–mediated microglial neurotoxicity via lowering of tumor necrosis factor–α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

scholarly journals Intracerebroventricular Infusion of Gangliosides Augments the Adult Neural Stem Cell Pool in Mouse Brain

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141988485
Author(s):  
Yutaka Itokazu ◽  
Dongpei Li ◽  
Robert K. Yu
Keyword(s):  
Mouse Brain ◽  
Expression Profiles ◽  
Normal Brain ◽  
Behavioral Deficits ◽  
Adult Neural Stem Cell ◽  
Intracerebroventricular Infusion ◽  
5Xfad Mouse ◽  
Developing Mouse Brain ◽  
Ganglioside Gd3

We previously reported that ganglioside GD3 is the predominant species in neural stem cells (NSCs) and reduced postnatal NSC pools are observed in both the subventricular zone and dentate gyrus (DG) of GD3-synthase knockout (GD3S-KO) mouse brains. Specifically, deficiency of GD3 in GD3S-KO animals revealed a dramatic reduction in cellularity in the DG of the hippocampus of the developing mouse brain, resulting in severe behavioral deficits in these animals. To further evaluate the functional role of GD3 in postnatal brain, we performed rescue experiments by intracerebroventricular infusion of ganglioside GD3 in adult GD3S-KO animals and found that it could restore the NSC pools and enhance the NSCs for self-renewal. Furthermore, 5xFAD mouse model was utilized, and GD3 restored NSC numbers and GM1 promoted neuronal differentiation. Our results thus demonstrate that exogenously administered gangliosides are capable to restore the function of postnatal NSCs. Since ganglioside expression profiles are associated not only with normal brain development but also with pathogenic mechanisms of diseases, such as Alzheimer’s disease, we anticipate that the administration of exogenous gangliosides, such as GD3 and GM1, may represent a novel and effective strategy for promoting adult neurogenesis in damaged brain for disease treatment.

scholarly journals Knockdown lncRNA DLEU1 Inhibits Gliomas Progression and Promotes Temozolomide Chemosensitivity by Regulating Autophagy

2020 ◽  
Vol 11 ◽  
Author(s):  
Qiao-Li Lv ◽  
Li-Chong Wang ◽  
Dang-Chi Li ◽  
Qian-Xia Lin ◽  
Xiao-Li Shen ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Normal Brain ◽  
Mesenchymal Transition ◽  
Cycle Arrest ◽  
Underlying Mechanisms ◽  
Multiple Drugs ◽  
Emt Markers ◽  
Brain Tissues

Gliomas are the most fatal malignant cerebral tumors. Temozolomide (TMZ), as the primary chemotherapy drug, has been widely used in clinics. However, resistance of TMZ still remains to poor defined. LncRNAs have been reported to play crucial roles in progression of various cancers and resistance of multiple drugs. However, the biological function and underlying mechanisms of most lncRNAs in glioma still remains unclear. Based on the TCGA database, a total of 94 differentially expressed lncRNAs, including 16 up-regulated genes and 78 downregulated genes were identified between gliomas and normal brain tissues. Subsequently, lncRNA DLEU1, HOTAIR, and LOC00132111 were tested to be significantly related to overall survival (OS) between high- and low-expression groups. Additionally, we verified that lncRNA DLEU1 was high expressed in 108 gliomas, compared with 19 normal brain tissues. And high expression of lncRNA DLEU1 predicted a poor prognosis (HR = 1.703, 95%CI: 1.133–2.917, p-value = 0.0159). Moreover, functional assays revealed that knockdown of lncRNA DLEU1 could suppress the proliferation by inducing cell cycle arrest at G1 phase and reducing the S phase by down-regulating the CyclinD1 and p-AKT, as the well as migration and invasion by inhibiting the epithelial–mesenchymal transition (EMT) markers, such as ZEB1, N-cadherin, β-catenin and snail in glioma cells. Furthermore, silencing lncRNA DLEU1 suppressed TMZ-activated autophagy via regulating the expression of P62 and LC3, and promoted sensitivity of glioma cells to TMZ by triggering apoptosis. Conclusively, our study indicated that lncRNA DLEU1 might perform as a prognostic potential target and underlying therapeutic target for sensitivity of glioma to TMZ.

scholarly journals Prefrontal Cortex in Learning to Overcome Generalized Fear

2015 ◽  
Vol 9 ◽  
pp. JEN.S26227 ◽  
Author(s):  
Edward Korzus
Keyword(s):  
Prefrontal Cortex ◽  
Discrimination Learning ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Camp Response Element Binding ◽  
Normal Brain ◽  
Camp Response Element ◽  
Brain Functioning ◽  
Element Binding Protein

Normal brain functioning relies critically on the ability to control appropriate behavioral responses to fearful stimuli. Overgeneralized fear is the major symptom of anxiety disorders including posttraumatic stress disorder. This review describes recent data demonstrating that the medial prefrontal cortex (mPFC) plays a critical role in the refining of cues that drive the acquisition of fear response. Recent studies on molecular mechanisms that underlie the role of mPFC in fear discrimination learning are discussed. These studies suggest that prefrontal N-methyl-D-aspartate receptors expressed in excitatory neurons govern fear discrimination learning via a mechanism involving cAMP response element-binding protein-dependent engagement of acetyltransferase.

Myelosuppresive Effects of Interferon [slpha] and Transforming Growth Factor β Can Be Reversed by Novel p38 MAPK Inhibitor SD-282 through Inhibition of Cell Cycle Arrest.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4229-4229
Author(s):  
Mani Mohindru ◽  
Perry Pahanish ◽  
Robert Collins ◽  
Tony Navas ◽  
Linda Higgins ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Type I ◽  
P38 Inhibitor ◽  
Cycle Arrest

Abstract Cytokines play important roles in the regulation of normal hematopoiesis and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of cells of different hematopoietic lineages. Even though the effects of Type I Interferons (IFNs α,β) and Transforming Growth Factor βs (TGF βs) as negative regulators of hematopoiesis are well documented, the exact molecular mechanisms by which such effects occur remain unknown. Our previous studies had shown that pharmacological inhibition of the p38 MAPK with commercially available inhibitors SB203580 and SB 202190 was able to reverse the myelosuppresion caused by IFN and TGF β. These inhibitors cannot be used in human studies due to toxicity and are also questioned for their selectivity in inhibiting the p38 MAPK. Thus, to confirm the role of p38 MAPK in regulating hematopoeisis, we conducted experiments with SD-282, a more potent and selective inhibitor of p38 α. SD-282 also performs very similarly in animal and cell models to a p38 inhibitor now in the clinic. Our results show that SD-282 is able to inhibit p38 MAPK selectively in primary human erythroid progenitors (at CFU-E stage of maturation) and suppress activation of downstream kinase MapKapK-2 after IFN α stimulation. In methycellulose clonogenic assays with mobilized CD34+ cells, IFN α treatment resulted in marked suppression of both erythroid (BFU-E) and myeloid (CFU-GM) colonies, which could be reversed in the presence of p38 inhibitor SD-282. In a similar manner TGF-β2 was not able to effectively inhibit both erythroid and myeloid colonies in the presence of p38 blockade by SD-282. In further studies, we demonstrate that the primary mechanism by which the p38 MAPK pathway mediates IFN mediated hematopoietic suppression is by regulation of cell cycle progression and is unrelated to induction of apoptosis. Treatment with p38 inhibitors led to significantly lesser numbers of cells in G0/G1 phase of cell cycle arrest induced by exposure to IFN α. Altogether, these findings confirm that the p38 MAPK signalling pathway is a common effector for type I IFN and TGF beta signaling in human hematopoietic progenitors and plays a critical role in the induction of the suppressive effects of these cytokines on normal hematopoiesis. Our studies also provide a rationale for the use of SD-282 and other p38 inhibitors in cytokine mediated hematological diseases.

scholarly journals Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Gabby Rudenko
Keyword(s):  
Information Transfer ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Scale Up ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Protein Partners

Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, forming trans-complexes spanning the synaptic cleft or cis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

scholarly journals 3024 Osteocyte-derived CXCL12 is Essential for Load-Induced Bone Formation in Adult Mice

2019 ◽  
Vol 3 (s1) ◽  
pp. 111-111 ◽  
Author(s):  
Pamela Cabahug Zuckerman ◽  
Chao Liu ◽  
Emily Fang ◽  
Alesha B Castillo
Keyword(s):  
New York ◽  
Bone Formation ◽  
Critical Role ◽  
New York University ◽  
Cxcl12 Expression ◽  
Male And Female ◽  
Female Mice ◽  
Adult Mice ◽  
Basal Bone ◽  
Underlying Mechanisms

OBJECTIVES/SPECIFIC AIMS: Our aim is to test whether osteocyte-specific CXCL12 expression is critical to exercise-driven bone formation. METHODS/STUDY POPULATION: All procedures were approved by the NEW YORK UNIVERSITY Institutional Animal Care and Use Committee. We generated male and female mice in which CXCL12 was deleted from OCYs (CXCL12ΔOCY) by crossing CXCL12 floxed mice and 10kb DMP1-Cre transgenic mice (gifts from Drs. Geoffrey Gurtner and Lynda Bonewald, respectively). The 10kb DMP1-Cre has been shown to be robustly expressed in odontoblasts and OCYs, with little to no activity in cells from non-mineralized tissues (Lu+ J Dent Res 2007). Growing male and female mice (n=3-8/group) were given fluorochrome labels every two weeks between 4-16 weeks of age, to monitor the role of CXCL12 during development. A second group, of adult 16-week-old mice (n=5/group), were subjected to tibial axial cyclic loading (1200µɛ, 2Hz, 120cycles, 3days/wk for 2 wks) (Liu+ Bone 2018). Basal and load-induced periosteal (Ps) and endosteal (Es) mineralizing surface (MS/BS, %), mineral apposition (MAR, µm/day) and bone formation rates (BFR/BS, µm3/µm2/year) were calculated (Dempster+ JBMR.2013) at mid-length. RESULTS/ANTICIPATED RESULTS: No significant differences were detected in basal bone formation during development. However, relative load-induced Ps MAR (rMAR) was reduced by 50% in female (p=0.02) and 75% in male (p=0.002) CXCL12ΔOCY mice; and similarly, Ps rBFR/BS was reduced by 50% in female (p=0.01) and 70% in male (p=0.001) CXCL12ΔOCY mice (Figure 1). Es bone formation was not affected by CXCL12 deletion. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, osteocyte-specific CXCL12 expression plays a critical role in exercise-driven periosteal new bone formation, suggesting that CXCL12 signaling may positively regulate osteogenic differentiation and/or mature osteoblast function. Further underlying mechanisms are currently being explored. Thus, osteocyte-specific CXCL12 signaling may be a promising target to enhance load-induced bone formation in patients with compromised ability to form new bone.

scholarly journals Brain Water Mobility Decreases after Astrocytic Aquaporin-4 Inhibition Using RNA Interference

2010 ◽  
Vol 31 (3) ◽  
pp. 819-831 ◽  
Author(s):  
Jérôme Badaut ◽  
Stephen Ashwal ◽  
Arash Adami ◽  
Beatriz Tone ◽  
Rebecca Recker ◽  
...  
Keyword(s):  
Rna Interference ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Water Diffusion ◽  
Cell Swelling ◽  
Normal Brain ◽  
Water Mobility ◽  
Aqp4 Expression ◽  
Apparent Diffusion ◽  
Adc Values

Neuroimaging with diffusion-weighted imaging is routinely used for clinical diagnosis/prognosis. Its quantitative parameter, the apparent diffusion coefficient (ADC), is thought to reflect water mobility in brain tissues. After injury, reduced ADC values are thought to be secondary to decreases in the extracellular space caused by cell swelling. However, the physiological mechanisms associated with such changes remain uncertain. Aquaporins (AQPs) facilitate water diffusion through the plasma membrane and provide a unique opportunity to examine the molecular mechanisms underlying water mobility. Because of this critical role and the recognition that brain AQP4 is distributed within astrocytic cell membranes, we hypothesized that AQP4 contributes to the regulation of water diffusion and variations in its expression would alter ADC values in normal brain. Using RNA interference in the rodent brain, we acutely knocked down AQP4 expression and observed that a 27% AQP4-specific silencing induced a 50% decrease in ADC values, without modification of tissue histology. Our results demonstrate that ADC values in normal brain are modulated by astrocytic AQP4. These findings have major clinical relevance as they suggest that imaging changes seen in acute neurologic disorders such as stroke and trauma are in part due to changes in tissue AQP4 levels.

scholarly journals Loss of ASH1L in developing brains causes autistic-like behaviors in a mouse model

2020 ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B Aljazi ◽  
Yan Wu ◽  
Adam J Moeser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Causal Link ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Critical Function ◽  
Developmental Defects ◽  
Neurodevelopmental Disease

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causal link between ASH1L mutations and ASD/ID remains undetermined. Here we show loss of ASH1L in developing mouse brains is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

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