“Neurodevelopment in a dish” Elucidates the Mechanisms of Autism Spectrum Disorder

2017 ◽  
Vol 41 (S1) ◽  
pp. s795-s795
Author(s):  
M. Ilieva ◽  
M. Kamand ◽  
K. Kolev ◽  
S.L. Forsberg ◽  
Å.F. Svenningsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Environmental Factors ◽  
Brain Development ◽  
Behavioral Flexibility ◽  
Autism Spectrum ◽  
Patient Specific ◽  
Cellular Models ◽  
The Brain

IntroductionAutism spectrum disorders (ASD) is a group of neurodevelopmental disorders characterized by deficits in social cognition, communication, and behavioral flexibility. Most of the cases appear to be caused by the combination of autism risk genes and environmental factors affecting early embryonal brain development. The current animal and 2D cellular models are not able to recapitulate the complex integrity of the developing brain. Therefore a model of the brain that can cast a light on the pathological processes during brain development is of a high need.Aim and objectivesThe aim of our research is to develop a three-dimensional brain organotypic system (brain organoids) for culturing patient's derived induced pluripotent stem cells (iPSC).MethodologyWe propose a multidisciplinary approach, involving the generation of patient specific iPSC from somatic cells (fibroblasts) and 3D culturing techniques to build a complex “humanized” in vitro platform for ASD research. Further we will investigate differences in gene expression of potential disease related markers and cellular phenotype between autistic patients and controls.ResultsBrain organoids have the ability to recreate the right complexity of the brain. On the cellular and gene expression level, organoids demonstrate a high similarity to the neurodevelopment in vivo and can therefore recapitulate early stages of the neurogenesis.ConclusionTo date organoids are the most relevant cellular in vitro platform for the understanding the mechanisms behind ADS pathology. Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Yukio Ago ◽  
Satoshi Asano ◽  
Hitoshi Hashimoto ◽  
James A. Waschek
Keyword(s):  
Synaptic Plasticity ◽  
Brain Development ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Autism Spectrum ◽  
Cellular Models ◽  
Pituitary Adenylate Cyclase ◽  
Innervation Patterns ◽  
The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) is a multifunctional neuropeptide involved in brain development and synaptic plasticity. With respect to PACAP function, most attention has been given to that mediated by its specific receptor PAC1 (ADCYAP1R1). However, PACAP also binds tightly to the high affinity receptors for vasoactive intestinal peptide (VIP, VIP), called VPAC1 and VPAC2 (VIPR1 and VIPR2, respectively). Depending on innervation patterns, PACAP can thus interact physiologically with any of these receptors. VPAC2 receptors, the focus of this review, are known to have a pivotal role in regulating circadian rhythms and to affect multiple other processes in the brain, including those involved in fear cognition. Accumulating evidence in human genetics indicates that microduplications at 7q36.3, containing VIPR2 gene, are linked to schizophrenia and possibly autism spectrum disorder. Although detailed molecular mechanisms have not been fully elucidated, recent studies in animal models suggest that overactivation of the VPAC2 receptor disrupts cortical circuit maturation. The VIPR2 linkage can thus be potentially explained by inappropriate control of receptor signaling at a time when neural circuits involved in cognition and social behavior are being established. Alternatively, or in addition, VPAC2 receptor overactivity may disrupt ongoing synaptic plasticity during processes of learning and memory. Finally, in vitro data indicate that PACAP and VIP have differential activities on the maturation of neurons via their distinct signaling pathways. Thus perturbations in the balance of VPAC2, VPAC1, and PAC1 receptors and their ligands may have important consequences in brain development and plasticity.

scholarly journals Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1208 ◽  
Author(s):  
Michael J. Garabedian ◽  
Charles A. Harris ◽  
Freddy Jeanneteau
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Health And Disease ◽  
And Behavior ◽  
External Signals ◽  
The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

Antisense Oligodeoxynucleotide Technology: Potential Use for the Treatment of Malignant Brain Tumors

1998 ◽  
Vol 5 (2) ◽  
pp. 163-170 ◽  
Author(s):  
Herbert H. Engelhard
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Relevant Information ◽  
In Vivo Studies ◽  
Antisense Oligodeoxynucleotide ◽  
Malignant Brain Tumors ◽  
Antisense Odns ◽  
The Brain

Background: Antisense oligodeoxynucleotides (ODNs) have been proposed as a new therapy for patients with cancer, including malignant brain tumors. Antisense ODNs are taken up by tumor cells and selectively block gene expression. Use of ODNs for brain tumors is attractive due to their theoretical specificity, relative ease of production and, to date, paucity of reported adverse effects. This article presents current information regarding antisense ODNs and their possible future use for the treatment of brain tumors. Methods: The available published experimental and clinical information regarding antisense ODN treatment of glioblastoma cells and administration into the central nervous system (CNS) was reviewed. Other clinically relevant information pertaining to the molecular biology of antisense ODNs was also collected and summarized. Results: Targets for antisense ODN therapy in malignant glioma cells have included c-myc, c-myb, c-sis, c-erb B, CD44, p34cdc2, bFGF, PDGF, TGF-beta, IGF-1, PKC-alpha tumor necrosis factor, urokinase, and S100beta protein. Few in vivo studies of ODN treatment of brain tumors have yet been reported. Systemically administered ODNs enter the brain only in extremely small quantities; therefore, microinfusion into the brain has been recommended. Conclusions: Antisense ODNs have been used successfully to block glioblastoma gene expression in vitro and expression of multiple genes within the CNS of experimental animals. Upcoming clinical trials will address the safety of antisense ODN use against malignant brain tumors.

scholarly journals Adipogenesis: new insights into brown adipose tissue differentiation

2013 ◽  
Vol 51 (3) ◽  
pp. T75-T85 ◽  
Author(s):  
Stefania Carobbio ◽  
Barry Rosen ◽  
Antonio Vidal-Puig
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Embryonic Stem ◽  
Genetically Engineered ◽  
Patient Specific ◽  
Murine Models ◽  
Cellular Models ◽  
Brown Adipose

Confirmation of the presence of functional brown adipose tissue (BAT) in humans has renewed interest in investigating the potential therapeutic use of this tissue. The finding that its activity positively correlates with decreased BMI, decreased fat content, and augmented energy expenditure suggests that increasing BAT mass/activity or browning of white adipose tissue (WAT) could be a strategy to prevent or treat obesity and its associated morbidities. The challenge now is to find a safe and efficient way to develop this idea. Whereas BAT has being widely studied in murine models bothin vivoandin vitro, there is an urgent need for human cellular models to investigate BAT physiology and functionality from a molecular point of view. In this review, we focus on the latest insights surrounding BAT development and activation in rodents and humans. Then, we discuss how the availability of murine models has been essential to identify BAT progenitors and trace their lineage. Finally, we address how this information can be exploited to develop human cellular models for BAT differentiation/activation. In this context, human embryonic stem and induced pluripotent stem cells-based cellular models represent a resource of great potential value, as they can provide a virtually inexhaustible supply of starting material for functional genetic studies, -omics based analysis and validation of therapeutic approaches. Moreover, these cells can be readily genetically engineered, opening the possibility of generating patient-specific cellular models, allowing the investigation of the influence of different genetic backgrounds on BAT differentiation in pathological or in physiological states.

scholarly journals Altered expression of Armet and Mrlp51 in the oocyte, preimplantation embryo, and brain of mice following oocyte in vitro maturation but postnatal brain development and cognitive function are normal

Reproduction ◽  
2011 ◽  
Vol 142 (3) ◽  
pp. 401-408 ◽  
Author(s):  
Ning Wang ◽  
Liya Wang ◽  
Fang Le ◽  
Qitao Zhan ◽  
Yingming Zheng ◽  
...  
Keyword(s):  
Brain Development ◽  
Early Stage ◽  
Suppressive Subtractive Hybridization ◽  
Control Group ◽  
Newborn Mice ◽  
Altered Expression ◽  
Developmental Potential ◽  
The Brain

Despite the efforts to recapitulate the follicle environment, oocytes from in vitro maturation (IVM) have poorer developmental potential than those matured in vivo and the effects on the resultant offspring are of concern. The aim of this study was to determine altered gene expression in oocytes following IVM and to evaluate the expression of the arginine rich, mutated in early stage of tumors gene (Armet) and mitochondrial ribosomal protein L51 (Mrpl51) in embryos and brains of fetal/postnatal mice and the brain development of IVM offspring. An IVM mouse model was established while oocytes matured in vivo were used as the controls. Suppressive subtractive hybridization (SSH) and RT-PCR/western blot were used to analyze the differential expression of genes/proteins between IVM and the control group. HE staining and water maze were used to assess the histological changes in brain tissue and cognition of the offspring. The rates of fertilization, cleavage, and live birth were significantly decreased in IVM group. Thirteen genes were upregulated in IVM oocytes compared with the control, including Armet and Mrpl51. The higher level of Armet in IVM oocytes was retained in brain of newborn mice, which could be related to the upregulation of activating transcription factor 6 (Atf6) and X-box binding protein 1 (Xbp1), while Mrpl51 was expressed normally in brain of postnatal mice. No significant differences were detected in brain weight, neuronal counts, and the cognition in the offspring between the two groups. The present results suggested that IVM could affect the pregnancy outcome and the Armet and Mrpl51 gene/protein expression. The change in Armet expression lasted while the change of Mrpl51 disappeared after birth. However, the brain development of the offspring seemed to be unaffected by IVM.

scholarly journals CHD8 Regulates Cellular Homeostasis and Neuronal Function Genes Across Multiple Models of CHD8 Haploinsufficiency

2018 ◽  
Author(s):  
A. Ayanna Wade ◽  
Kenneth Lim ◽  
Rinaldo Catta-Preta ◽  
Alex S. Nord
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Chromatin Remodeling ◽  
De Novo ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Cell Functions ◽  
High Affinity

ABSTRACTThe packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Recent sequencing of patient mutations has linked de novo loss-of-function mutations to chromatin remodeling factors with specific, causal roles in neurodevelopmental disorders. Characterizing cellular and molecular phenotypes arising from haploinsufficiency of chromatin remodeling factors could reveal convergent mechanisms of pathology. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeling factor gene and has among the highest de novo loss-of-function mutations rates in patients with autism spectrum disorder (ASD). Mutations to CHD8 are expected to drive neurodevelopmental pathology through global disruptions to gene expression and chromatin state, however, mechanisms associated with CHD8 function have yet to be fully elucidated. We analyzed published transcriptomic and epigenomic data across CHD8 in vitro and in vivo knockdown and knockout models to identify convergent mechanisms of gene regulation by CHD8. We found reproducible high-affinity interactions of CHD8 near promoters of genes necessary for basic cell functions and gene regulation, especially chromatin organization and RNA processing genes. Overlap between CHD8 interaction and differential expression suggests that reduced dosage of CHD8 directly relates to decreased expression of these genes. In addition, genes important for neuronal development and function showed consistent dysregulation, though there was a reduced rate and decreased affinity for CHD8 interactions near these genes. This meta-analysis verifies CHD8 as a critical regulator of gene expression and reveals a consistent set of high affinity CHD8 interaction targets observed across human and mouse in vivo and in vitro studies. Our findings highlight novel core functions of CHD8 and indicate direct and downstream gene regulatory impacts that are likely to be associated with neuropathology underlying CHD8-associated neurodevelopmental disorder.

Chemical and biological methods for probing the structure and functions of polysialic acids

2018 ◽  
Vol 2 (3) ◽  
pp. 363-376 ◽  
Author(s):  
Surbhi Goswami ◽  
Shubham Parashar ◽  
Vandita Dwivedi ◽  
Asif Shajahan ◽  
Srinivasa-Gopalan Sampathkumar
Keyword(s):  
Brain Development ◽  
Neurological Disorders ◽  
Ex Vivo ◽  
Neuroblastoma Cells ◽  
Peripheral Tissues ◽  
Hybrid Strategy ◽  
The Brain ◽  
Structure And Functions

Owing to its poly-anionic charge and large hydrodynamic volume, polysialic acid (polySia) attached to neural cell adhesion molecule regulates axon–axon and axon–substratum interactions and signalling, particularly, in the development of the central nervous system (CNS). Expression of polySia is spatiotemporally regulated by the action of two polysialyl transferases, namely ST8SiaII and ST8SiaIV. PolySia expression peaks during late embryonic and early post-natal period and maintained at a steady state in adulthood in neurogenic niche of the brain. Aberrant polySia expression is associated with neurological disorders and brain tumours. Investigations on the structure and functions, over the past four decades, have shed light on the physiology of polySia. This review focuses on the biological, biochemical, and chemical tools available for polySia engineering. Genetic knockouts, endo-neuraminidases that cleave polySia, antibodies, exogenous expression, and neuroblastoma cells have provided deep insights into the ability of polySia to guide migration of neuronal precursors in neonatal brain development, neuronal clustering, axonal pathway guidance, and axonal targeting. Advent of metabolic sialic acid engineering using ManNAc analogues has enabled reversible and dose-dependent modulation polySia in vitro and ex vivo. In vivo, ManNAc analogues readily engineer the sialoglycans in peripheral tissues, but show no effect in the brain. A recently developed carbohydrate-neuroactive hybrid strategy enables a non-invasive access to the brain in living animals across the blood–brain barrier. A combination of recent advances in CNS drugs and imaging with ManNAc analogues for polySia modulation would pave novel avenues for understanding intricacies of brain development and tackling the challenges of neurological disorders.

scholarly journals Epigenetic Reprogramming Induced Pluripotency

2011 ◽  
Vol 3 (2) ◽  
pp. 93
Author(s):  
Anna Meiliana ◽  
Andi Wijaya
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Nuclear Transfer ◽  
Es Cells ◽  
Ips Cells ◽  
Genetic Alterations ◽  
Epigenetic Reprogramming ◽  
Patient Specific

BACKGROUND: The ability to reprogram mature cells to an embryonic-like state by nuclear transfer or by inducing the expression of key transcription factors has provided us with critical opportunities to linearly map the epigenetic parameters that are essential for attaining pluripotency.CONTENT: Epigenetic reprogramming describes a switch in gene expression of one kind of cell to that of another unrelated cell type. Early studies in frog cloning provided some of the first experimental evidence for reprogramming. Subsequent procedures included mammalian somatic cell nuclear transfer, cell fusion, induction of pluripotency by ectopic gene expression, and direct reprogramming. Through these methods it becomes possible to derive one kind of specialized cell (such as a brain cell) from another, more accessible tissue, such as skin in the same individual. This has potential applications for cell replacement without the immunosuppression treatments commonly required when cells are transferred between genetically different individuals.SUMMARY: Reprogramming with transcription factors offers tremendous promise for the future development of patient-specific pluripotent cells and for studies of human disease. The identification of optimized protocols for the differentiation of iPS cells and ES cells into multiple functional cell types in vitro and their proper engraftment in vivo will be challenged in the coming years. Given that the first small molecule approaches aimed at activating pluripotency genes have already been devised and that murine iPS cells have recently been derived by using non-integrative transient expression strategies of the reprogramming factors, we expect that human iPS cells without permanent genetic alterations will soon be generated.KEYWORDS: epigenetics, reprogramming, pluripotency, stem cells, iPS cells, chromatin, DNA methylation

scholarly journals S-adenosylmethionine modifies cocaine-induced DNA methylation and increases locomotor sensitization in mice

2013 ◽  
Vol 16 (9) ◽  
pp. 2053-2066 ◽  
Author(s):  
Kaili Anier ◽  
Alexander Zharkovsky ◽  
Anti Kalda
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Environmental Factors ◽  
Drug Addiction ◽  
Cpg Island ◽  
Individual Variability ◽  
Locomotor Sensitization ◽  
Reference Tissue

Abstract Several studies suggest that individual variability is a critical component underlying drug addiction as not all members of a population who use addictive substance become addicted. There is evidence that the overall epigenetic status of a cell (epigenome) can be modulated by a variety of environmental factors, such as nutrients and chemicals. Based on these data, our aim was to investigate whether environmental factors like S-adenosylmethionine (SAM) via affecting epigenome could alter cocaine-induced gene expression and locomotor sensitization in mice. Our results demonstrate that repeated SAM (10 mm/kg) pretreatment significantly potentiated cocaine-induced locomotor sensitization. Using mouse nucleus accumbens (NAc) tissue, whole-genome gene expression profiling revealed that repeated SAM treatment affected a limited number of genes, but significantly modified cocaine-induced gene expression by blunting non-specifically the cocaine response. At the gene level, we discovered that SAM modulated cocaine-induced DNA methylation by inhibiting both promoter-associated CpG-island hyper- and hypomethylation in the NAc but not in the reference tissue cerebellum. Finally, our in vitro and in vivo data show that the modulating effect of SAM is in part due to decreased methyltransferase activity via down-regulation of Dnmt3a mRNA. Taken together, our results suggest that environmental factors that affect the NAc-cell epigenome may alter the development of psychostimulant-induced addiction and this may explain, at least partly, why some individuals are more vulnerable to drug addiction.

Neurobiology of Autism Spectrum Disorders

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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