scholarly journals Regulation of Dendritic Synaptic Morphology and Transcription by the SRF Cofactor MKL/MRTF

2021 ◽  
Vol 14 ◽  
Author(s):  
Akiko Tabuchi ◽  
Daisuke Ihara
Keyword(s):  
Nervous System ◽  
Transcriptional Activation ◽  
Cortical Neurons ◽  
Serum Response Factor ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Fine Tuning ◽  
Actin Binding ◽  
Special Focus ◽  
Dendritic Complexity

Accumulating evidence suggests that the serum response factor (SRF) cofactor megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF) has critical roles in many physiological and pathological processes in various cell types. MKL/MRTF molecules comprise MKL1/MRTFA and MKL2/MRTFB, which possess actin-binding motifs at the N-terminus, and SRF-binding domains and a transcriptional activation domain (TAD) at the C-terminus. Several studies have reported that, in association with actin rearrangement, MKL/MRTF translocates from the cytoplasm to the nucleus, where it regulates SRF-mediated gene expression and controls cell motility. Therefore, it is important to elucidate the roles of MKL/MRTF in the nervous system with regard to its structural and functional regulation by extracellular stimuli. We demonstrated that MKL/MRTF is highly expressed in the brain, especially the synapses, and is involved in dendritic complexity and dendritic spine maturation. In addition to the positive regulation of dendritic complexity, we identified several MKL/MRTF isoforms that negatively regulate dendritic complexity in cortical neurons. We found that the MKL/MRTF isoforms were expressed differentially during brain development and the impacts of these isoforms on the immediate early genes including Arc/Arg3.1, were different. Here, we review the roles of MKL/MRTF in the nervous system, with a special focus on the MKL/MRTF-mediated fine-tuning of neuronal morphology and gene transcription. In the concluding remarks, we briefly discuss the future perspectives and the possible involvement of MKL/MRTF in neurological disorders such as schizophrenia and autism spectrum disorder.

scholarly journals Glutathione S-transferase Pi (Gstp) Proteins Regulate Neuritogenesis in the Developing Cerebral Cortex

2020 ◽  
Author(s):  
Xiaonan Liu ◽  
Sara M. Blazejewski ◽  
Sarah A. Bennison ◽  
Kazuhito Toyo-oka
Keyword(s):  
Cortical Neurons ◽  
Cortical Development ◽  
Apical Dendrite ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Jnk Signaling ◽  
Neurite Elongation ◽  
Neurite Initiation ◽  
Neurite Formation

AbstractGSTP proteins are metabolic enzymes involved in removal of oxidative stress and intracellular signaling and also have inhibitory effects on JNK activity. However, the functions of Gstp proteins in the developing brain are unknown. In mice, there are three Gstp proteins, Gstp1, 2 and 3, while there is only one GSTP in humans. By RT-PCR analysis, we found that Gstp1 was expressed beginning at E15.5 in the cortex, but Gstp2 and 3 started expressing at E18.5. Gstp 1 and 2 knockdown caused decreased neurite number in cortical neurons, implicating them in neurite initiation. Using in utero electroporation to knockdown Gstp1 and 2 in layer 2/3 pyramidal neurons in vivo, we found abnormal swelling of the apical dendrite at P3 and reduced neurite number at P15. Using time-lapse live imaging, we found that the apical dendrite orientation was skewed compared to the control, but these defects were ameliorated. Overexpression of Gstp 1 or 2 resulted in changes in neurite length, suggesting a role in neurite elongation. We explored the molecular mechanism and found that JNK inhibition rescued reduced neurite number caused by Gstp knockdown, indicating that Gstp regulates neurite formation through JNK signaling. Thus, we found novel functions of Gstp proteins in neurite initiation during cortical development. Furthermore, the overexpression experiments suggest different functions of Gstp1 and 2 in neurite elongation. Since previous studies have shown the potential implication of Gstp in Autism Spectrum Disorder, our findings will attract more clinical interests in Gstp proteins in neurodevelopmental disorders.SignificanceNeurite formation, including neurite initiation and elongation, is the first step of generating polarized neuronal morphology in developing neurons, and thus is essential for establishing a neuronal network. Therefore, it is crucial to understand the mechanisms of neurite formation. Limited studies have been performed to clarify the mechanisms of neurite formation, especially neurite initiation. In this present study, we report a novel, essential role of Gstp in neurite initiation in mouse cortical neurons in vitro and in vivo. We also found that Gstp regulates neurite formation via JNK signaling pathways. These findings not only provide novel functions of Gstp proteins in neuritogenesis during cortical development but also help us to understand the complexity of neurite formation.

Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

2017 ◽  
Vol 29 (2) ◽  
Author(s):  
Timothy R. Rice
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodevelopmental Disorders ◽  
System Development ◽  
Explanatory Power ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Special Focus ◽  
Important Mediator ◽  
Androgen Exposure

Abstract Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

Actin-binding coactivator MKL is involved in a novel signaling pathway for activin-regulated dendritic complexity of rat cortical neurons

2011 ◽  
Vol 71 ◽  
pp. e333
Author(s):  
Mitsuru Ishikawa ◽  
Naoki Nishijima ◽  
Hiroyuki Sakagami ◽  
Kunihiro Tsuchida ◽  
Miho Mizukoshi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cortical Neurons ◽  
Actin Binding ◽  
Rat Cortical Neurons ◽  
Dendritic Complexity

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.

Correlation Between DTI Findings and Volume of Corpus Callosum in Children with AUTISM

2019 ◽  
Vol 15 (9) ◽  
pp. 895-899 ◽  
Author(s):  
Hafize Otcu Temur ◽  
Ismail Yurtsever ◽  
Gozde Yesil ◽  
Rasul Sharifov ◽  
Fatih Temel Yilmaz ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Cortical Neurons ◽  
Diffusion Tensor ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Volume Measurements ◽  
Adc Values ◽  
Axonal Density ◽  
Area And Volume

Background: Autism Spectrum Disorder (ASD) is a complex developmental disorder in which neurological basis is largely unknown. The Corpus Callosum (CC) is the main commissure that connects the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. Aim: The aim of our study is to assess whether there were any changes in Corpus Callosum (CC) area and volume and to reveal the relationship between Diffusion Tensor Imaging (DTI) features in genu and splenium of corpus callosum in children with ASD. Methods: Eighteen patient and 15 controls were recruited. The volumetric sagittal TI images were used to provide measurements of midsagittal corpus callosum surface area while FA, MD, RD, and ADC values were extracted from genu and splenium of corpus callosum after which the correlation in the area and volume in ASD children was examined. Results: CC area and volume in children with ASD were decreased than controls. FA values obtained from the genu and splenum of CC were significantly lower and RD values were significantly higher. A positive correlation was observed between the FA of the genu and splenium and area and volume of the CC. There was a negative correlation between ADC, MD and RD of CC and area and volume measurements. Conclusion: The conclusions in the interrelations of morphometric and DTI data may demonstrate a likelihood of damages in the axons and cortical neurons. The results showed that there existed microstructural damages from the DTI findings. Furthermore, the decrease in FA could be a representation of the reduction in the myelination in nerve pathways, impaired integrity, reduced axonal density, and organization. Indeed, the changes in volumetric and microstructural of CC could be useful in evaluating underlying pathophysiology in children with autism.

scholarly journals The role of CPEB family proteins in the nervous system function in the norm and pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kozlov ◽  
Yulii V. Shidlovskii ◽  
Rudolf Gilmutdinov ◽  
Paul Schedl ◽  
Mariya Zhukova
Keyword(s):  
Nervous System ◽  
Gene Regulation ◽  
Neural Development ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mrna Transport ◽  
Ribonucleoprotein Complexes ◽  
Posttranscriptional Gene Regulation ◽  
Nervous System Function ◽  
Functional Features

AbstractPosttranscriptional gene regulation includes mRNA transport, localization, translation, and regulation of mRNA stability. CPEB (cytoplasmic polyadenylation element binding) family proteins bind to specific sites within the 3′-untranslated region and mediate poly- and deadenylation of transcripts, activating or repressing protein synthesis. As part of ribonucleoprotein complexes, the CPEB proteins participate in mRNA transport and localization to different sub-cellular compartments. The CPEB proteins are evolutionarily conserved and have similar functions in vertebrates and invertebrates. In the nervous system, the CPEB proteins are involved in cell division, neural development, learning, and memory. Here we consider the functional features of these proteins in the nervous system of phylogenetically distant organisms: Drosophila, a well-studied model, and mammals. Disruption of the CPEB proteins functioning is associated with various pathologies, such as autism spectrum disorder and brain cancer. At the same time, CPEB gene regulation can provide for a recovery of the brain function in patients with fragile X syndrome and Huntington's disease, making the CPEB genes promising targets for gene therapy.

scholarly journals Gut Microbiome-Based Analysis of Lipid A Biosynthesis in Individuals with Autism Spectrum Disorder: An In Silico Evaluation

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 688
Author(s):  
Abdulkadir Yusif Maigoro ◽  
Soojin Lee
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiome ◽  
In Silico ◽  
Lipid A ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Synthesis Rate ◽  
Special Focus ◽  
Control Subjects ◽  
Gastrointestinal Problems

The link between autism spectrum disorder (ASD) and the gut microbiome has received much attention, with special focus on gut–brain-axis immunological imbalances. Gastrointestinal problems are one of the major symptoms of ASD and are thought to be related to immune dysregulation. Therefore, in silico analysis was performed on mined data from 36 individuals with ASD and 21 control subjects, with an emphasis on lipid A endotoxin-producing bacteria and their lipopolysaccharide (LPS) metabolic pathways. Analysis of enzyme distribution among the 15 most abundant genera in both groups revealed that almost all these genera utilized five early-stage enzymes responsible for catalyzing the nine conserved lipid A synthesis steps. However, Haemophilus and Escherichia, which were significantly more abundant in individuals with ASD than in the control subjects, possess a complete set of essential lipid A synthesis enzymes. Furthermore, the 10 genera with the greatest increase in individuals with ASD showed high potential for producing late-stage lipid A products. Collectively, these results suggested that the synthesis rate of immunogenic LPS end products is likely to increase in individuals with ASD, which may be related to their gastrointestinal symptoms and elevated inflammatory conditions.

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