scholarly journals ASH1L REGULATES THE STRUCTURAL DEVELOPMENT OF NEURONAL CIRCUITRY BY MODULATING BDNF/TrkB SIGNALING IN HUMAN NEURONS

2020 ◽  
Author(s):  
Seon Hye Cheon ◽  
Allison M. Culver ◽  
Anna M. Bagnell ◽  
Foster D. Ritchie ◽  
Janay M. Clytus ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Epigenetic Mechanism ◽  
Neurotrophin Receptor ◽  
List Type ◽  
Structural Development ◽  
Neuronal Connectivity ◽  
Neuronal Morphogenesis ◽  
Human Neurons

SUMMARYAutism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes among the genes associated with ASD. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism. ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation. However, how mutations in ASH1L lead to deficits in neuronal connectivity associated with autism pathogenesis is not known. We report that ASH1L regulates neuronal morphogenesis by counteracting the catalytic activity of Polycomb Repressive complex 2 group (PRC2) in stem cell-derived human neurons. Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. This is overcome by inhibition of PRC2 activity, indicating a balance between the Trithorax group protein ASH1L and PRC2 activity determines neuronal morphology and connectivity. Thus, ASH1L epigenetically regulates neuronal connectivity by modulating the BDNF-TrkB signaling pathway, which likely contributes to the neurodevelopmental pathogenesis associated with ASD in patients with ASH1L mutations.eTOC BLURBCheon et al. report a novel epigenetic mechanism that implicates the counteracting activities of the evolutionarily conserved Trithorax (ASH1L) and Polycomb (PRC2) chromatin regulators, in the modulation of human neuronal connectivity by regulating the developmentally important TrkB-BDNF signaling pathway.HIGHLIGHTSASH1L regulates neuronal morphogenesis by modulating neurotrophin signalingCounteracting activities of Trithorax (ASH1L) and Polycomb (PRC2) affect neuronal arborizationLoss of ASH1L modulates growth cone size in human neurons

scholarly journals 14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling

2020 ◽  
Author(s):  
Sarah A. Bennison ◽  
Sara M. Blazejewski ◽  
Xiaonan Liu ◽  
Kazuhito Toyo-oka
Keyword(s):  
Calcium Signaling ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Cortical Connectivity ◽  
Neuronal Morphogenesis ◽  
Layer 2 ◽  
Neurite Formation ◽  
Activity Dependent

AbstractNeurite formation is the earliest stage of neuronal morphogenesis, where primitive dendrites and the primitive axon emerge from a spherical neuron and begin to elongate. Defective neuritogenesis is a contributing pathogenic mechanism behind a variety of neurodevelopmental disorders. Activity-dependent neuroprotective protein (Adnp) is essential to embryonic and postnatal brain development, and mutations in ADNP are among the most frequent underlying autism spectrum disorder (ASD). We found that knockdown of Adnp in vitro and in vivo in mouse layer 2/3 pyramidal neurons leads to increased neurite initiation and defective neurite elongation, suggesting that Adnp has distinct roles in each. In vivo analysis revealed that deficits begin at P0 and are sustained throughout development, the most notable of which include increased neurite stabilization, disrupted angle of the apical dendrite, increased basal dendrite number, and increased axon length. Because small changes in neuronal morphology can have large-scale effects on neuronal function and connectivity, we performed ex vivo calcium imaging to assess spontaneous function of layer 2/3 pyramidal neurons deficient in Adnp. This revealed that Adnp deficient neurons had a greater spontaneous calcium influx and a higher proportion of cells firing action potentials. Next, we utilized GRAPHIC, a novel synaptic tracing technology, to assess interhemispheric cortical connectivity. We found increased interhemispheric excitatory connectivity between Adnp deficient layer 2/3 pyramidal neurons. Because Adnp is a multifunctional protein with both transcription factor and cytoskeletal activity, we performed localization analysis of Adnp as neurons underwent neurite formation to probe the mechanism of our morphological defects. We found that Adnp is shuttled from the nucleus to the cytoplasm upon differentiation and this shuttling can be blocked via application of a global 14-3-3 inhibitor, difopein. Furthermore, we found that Adnp binds nuclear-cytoplasmic shuttle 14-3-3ε. We conclude that Adnp is shuttled from the nucleus to the cytoplasm by 14-3-3ε, where it regulates neuronal morphology, maturation, cortical connectivity, and calcium signaling.

scholarly journals P.135 Autism-associated mutations in SHANK2 increase synaptic connectivity and dendrite complexity in human neurons

2018 ◽  
Vol 45 (s2) ◽  
pp. S52-S52
Author(s):  
K Zaslavsky ◽  
W Zhang ◽  
E Deneault ◽  
M Zhao ◽  
DC Rodrigues ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Autism Spectrum ◽  
Dermal Fibroblasts ◽  
Neuronal Morphology ◽  
Synaptic Connectivity ◽  
Loss Of Function ◽  
Knock Out ◽  
Electrophysiological Properties ◽  
Dendrite Length ◽  
Human Neurons

Background: Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). However, their impact on the function of human neurons is unknown. Derivation of induced pluripotent stem cells (iPSC) from affected individuals permits generation of live neurons to answer this question. Methods: We generated iPSCs by reprogramming dermal fibroblasts of neurotypic and ASD-affected donors. To isolate the effect of SHANK2, we used CRISPR/Cas9 to knock out SHANK2 in control iPSCs and correct a heterozygous nonsense mutation in ASD-affected donor iPSCs. We then derived cortical neurons from SOX1+ neural precursor cells differentiated from these iPSCs. Using a novel assay that overcomes line-to-line variability, we compared neuronal morphology, total synapse number, and electrophysiological properties between SHANK2 mutants and controls. Results: Relative to controls, SHANK2 mutant neurons have increased dendrite complexity, dendrite length, total synapse number (1.5-2-fold), and spontaneous excitatory postsynaptic current (sEPSC) frequency (3-7.6-fold). Conclusions: ASD-associated heterozygous loss-of-function mutations in SHANK2 increase synaptic connectivity among human neurons by increasing synapse number and sEPSC frequency. This is partially supported by increased dendrite length and complexity, providing evidence that SHANK2 functions as a suppressor of dendrite branching during neurodevelopment.

scholarly journals Acceleration of TAA-Induced Liver Fibrosis by Stress Exposure Is Associated with Upregulation of Nerve Growth Factor and Glycopattern Deviations

2021 ◽  
Vol 22 (10) ◽  
pp. 5055
Author(s):  
Catalina Atorrasagasti ◽  
Flavia Piccioni ◽  
Sophia Borowski ◽  
Irene Tirado-González ◽  
Nancy Freitag ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Liver Damage ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Nerve Growth ◽  
Fibrotic Process ◽  
Ngf Signaling

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased β1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.

scholarly journals ChIP-seq Profiling Identifies Histone Deacetylase 2 Targeting Genes Involved in Immune and Inflammatory Regulation Induced by Calcitonin Gene-Related Peptide in Microglial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xingjing Guo ◽  
Dan Chen ◽  
Shuhong An ◽  
Zhaojin Wang
Keyword(s):  
Signaling Pathway ◽  
Histone Deacetylase ◽  
Calcitonin Gene Related Peptide ◽  
Epigenetic Mechanism ◽  
Microglial Cells ◽  
Transcriptional Level ◽  
Gene Promoters ◽  
Histone Deacetylase 2 ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP) is a mediator of microglial activation at the transcriptional level. The involvement of the epigenetic mechanism in this process is largely undefined. Histone deacetylase (HDAC)1/2 are considered important epigenetic regulators of gene expression in activated microglia. In this study, we examined the effect of CGRP on HDAC2-mediated gene transcription in microglial cells through the chromatin immunoprecipitation sequencing (ChIP-seq) method. Immunofluorescence analysis showed that mouse microglial cells (BV2) expressed CGRP receptor components. Treatment of microglia with CGRP increased HDAC2 protein expression. ChIP-seq data indicated that CGRP remarkably altered promoter enrichments of HDAC2 in microglial cells. We identified 1271 gene promoters, whose HDAC2 enrichments are significantly altered in microglia after CGRP treatment, including 1181 upregulating genes and 90 downregulating genes. Bioinformatics analyses showed that HDAC2-enriched genes were mainly associated with immune- and inflammation-related pathways, such as nitric oxide synthase (NOS) biosynthetic process, retinoic acid-inducible gene- (RIG-) like receptor signaling pathway, and nuclear factor kappa B (NF-κB) signaling pathway. The expression of these key pathways (NOS, RIG-I, and NF-κB) were further verified by Western blot. Taken together, our findings suggest that genes with differential HDAC2 enrichments induced by CGRP function in diverse cellular pathways and many are involved in immune and inflammatory responses.

scholarly journals Critical Role for Kalirin in Nerve Growth Factor Signaling through TrkA

2005 ◽  
Vol 25 (12) ◽  
pp. 5106-5118 ◽  
Author(s):  
Kausik Chakrabarti ◽  
Rong Lin ◽  
Noraisha I. Schiller ◽  
Yanping Wang ◽  
David Koubi ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Pc12 Cells ◽  
Critical Role ◽  
Neuronal Morphology ◽  
Neurotrophin Receptor ◽  
General Mechanism ◽  
Pleckstrin Homology Domain ◽  
Pleckstrin Homology ◽  
Nerve Growth

ABSTRACT Kalirin is a multidomain guanine nucleotide exchange factor (GEF) that activates Rho proteins, inducing cytoskeletal rearrangement in neurons. Although much is known about the effects of Kalirin on Rho GTPases and neuronal morphology, little is known about the association of Kalirin with the receptor/signaling systems that affect neuronal morphology. Our experiments demonstrate that Kalirin binds to and colocalizes with the TrkA neurotrophin receptor in neurons. In PC12 cells, inhibition of Kalirin expression using antisense RNA decreased nerve growth factor (NGF)-induced TrkA autophosphorylation and process extension. Kalirin overexpression potentiated neurotrophin-stimulated TrkA autophosphorylation and neurite outgrowth in PC12 cells at a low concentration of NGF. Furthermore, elevated Kalirin expression resulted in catalytic activation of TrkA, as demonstrated by in vitro kinase assays and increased NGF-stimulated cellular activation of Rac, Mek, and CREB. Domain mapping demonstrated that the N-terminal Kalirin pleckstrin homology domain mediates the interaction with TrkA. The effects of Kalirin on TrkA provide a molecular basis for the requirement of Kalirin in process extension from PC12 cells and for previously observed effects on axonal extension and dendritic maintenance. The interaction of TrkA with the pleckstrin homology domain of Kalirin may be one example of a general mechanism whereby receptor/Rho GEF pairings play an important role in receptor tyrosine kinase activation and signal transduction.

An alert in the psycho-social-health intervention. A graphic testimony of a real case with autism spectrum disorder

2011 ◽  
Vol 26 (S2) ◽  
pp. 758-758
Author(s):  
J.A. García ◽  
A.S. Raya ◽  
E.S. del Arco
Keyword(s):  
Autism Spectrum ◽  
Real Case ◽  
List Type ◽  
Type Number ◽  
High Functioning ◽  
The Family ◽  
Pertinent Information ◽  
New Challenges ◽  
Professional Intervention

The graphic papers of Pablo, 14 years, diagnosed of autism of high functioning, serve as a sign of alert when facing what underlies after the specializing professional intervention.A few letters, a few drawings, and a few words that show the powerlessness, the suffering and the absence of contextual specific adequacy.In this work we study, from the analysis of a real case, some excellent aspects in the psychosociosanitary attention, such as:-The need for compilation of pertinent information-The need for elimination of prejudices-The need for respect to the family-The need for specialized formation-The need for search of a shared communicative code-The need for search of strategies of social interaction-The need for empathy-The need for search of contextual specific adequacy-The need for rigorous rules in the physical containment.-The need of a turned over of adapted information-The need to respect the psychoevolutive situation of the patient-The need to give priority to the person on the illness.A testimony that should serve as a warning for those institutions, administrations and professionals who are thinking of having put all the resources to its scope.A testimony that should serve to contribute information and new challenges to those other professionals who do not stop their determination of conceptual and/or clinical anxious research.

scholarly journals Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann Herault
Keyword(s):  
Object Recognition ◽  
Recognition Memory ◽  
Mouse Models ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
List Type ◽  
Object Recognition Memory

ABSTRACTGene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.HIGHLIGHTS- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models- Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests- Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models

Abstract 19285: Notch1 Haploinsufficiency Increases Risk of Congenital Heart Defects in the Setting of Maternal Diabetes by an Epigenetic Mechanism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Madhumita Basu ◽  
Kevin Bosse ◽  
Vidu Garg
Keyword(s):  
Signaling Pathway ◽  
Congenital Heart ◽  
Genetic Interaction ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Epigenetic Mechanism ◽  
Luciferase Reporter ◽  
Environment Interaction ◽  
Mrna Levels ◽  
Dependent Manner

Congenital heart disease (CHD) is the most common type of birth defect. Epidemiologic studies have shown the importance of genetic and environmental factors in the multifactorial etiology of CHD. Maternal diabetes mellitus (DM) is one of the non-genetic risk factors that predisposes to CHD predominantly cardiac septation and cardiac outflow tract defects. DM is known to be associated with endothelial cell dysfunction and we recently demonstrated a genetic interaction between endothelial nitric oxide synthase and Notch1, which encodes a receptor that functions in an important cardiac developmental signaling pathway. We hypothesized that maternal DM in the setting of Notch1 heterozygosity of the developing embryo will predispose to CHD. Notch1 +/- embryos (E13.5) exposed to maternal DM demonstrated an increased incidence (86%) of ventricular septal defects compared to wildtype littermates (22%) (Table). Gene expression studies in non-diabetic wildtype, diabetic wildtype and Notch1 +/- embryos showed DM was associated with decreased Notch1 mRNA levels and upregulation in Jarid2, a histone H3K9 demethylase known to regulate Notch1. In H9C2 and endocardial-derived cells and chick embryos, we showed that hyperglycemia led to decreased expression of Notch1 and its downstream targets in a dose-dependent manner. Similarly, Jarid2 mRNA levels increased with high glucose. Furthermore, we found reduced luciferase reporter activity in cells transfected with a constitutively active Notch1 intracellular domain with hyperglycemia. Studies demonstrating the relative enrichment of Jarid2 on Notch1 locus with hyperglycemia by ChIP-qPCR will also be presented. Our findings reveal that maternal DM disrupts cardiac development by deregulating the Notch1 signaling pathway and suggest that this gene-environment interaction is mediated by an epigenetic mechanism involving Jarid2 providing the first mechanistic insights for this association.

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