scholarly journals Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex

2021 ◽  
Vol 22 (24) ◽  
pp. 13201
Author(s):  
Songphon Kanlayaprasit ◽  
Surangrat Thongkorn ◽  
Pawinee Panjabud ◽  
Depicha Jindatip ◽  
Valerie W. Hu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Prefrontal Cortex ◽  
Bisphenol A ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Postmortem Brain ◽  
Dependent Manner ◽  
Distribution Analysis ◽  
Docking Analysis ◽  
Specific Effects

Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

scholarly journals Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

2018 ◽  
Author(s):  
Ashley M. Ingiosi ◽  
Taylor Wintler ◽  
Hannah Schoch ◽  
Kristan G. Singletary ◽  
Dario Righelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Sleep Problems ◽  
Wheel Running ◽  
The United States ◽  
Autism Spectrum ◽  
Wheel Running Activity ◽  
Falling Asleep ◽  
Circadian Transcription

AbstractAutism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Dec2, Hlf, Tef, and Reverbα. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall our study shows that Shank3 is an important modulator of sleep and clock gene expression.

scholarly journals (R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism

2019 ◽  
Vol 22 (10) ◽  
pp. 665-674 ◽  
Author(s):  
Yukio Ago ◽  
Wataru Tanabe ◽  
Momoko Higuchi ◽  
Shinji Tsukada ◽  
Tatsunori Tanaka ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Ampa Receptor ◽  
Dopamine Release ◽  
Molecular Mechanisms ◽  
In Vivo Microdialysis ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Independent Mechanism ◽  
Dose Dependent

Abstract Background Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine’s action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. Methods The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. Results (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. Conclusions (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi24
Author(s):  
Kelly Mitchell ◽  
Joseph Alvarado ◽  
Christopher Goins ◽  
Steven Martinez ◽  
Jonathan Macdonald ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Self Renewal ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

scholarly journals Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms

2020 ◽  
Author(s):  
Takafumi Yumoto ◽  
Misaki Kimura ◽  
Ryota Nagatomo ◽  
Tsukika Sato ◽  
Shun Utsunomiya ◽  
...  
Keyword(s):  
Cell Surface ◽  
Psychiatric Disorders ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Proteolytic Processing ◽  
Synaptic Activity ◽  
Common Mechanism ◽  
Dependent Manner

Abstract Background: Several genetic alterations, including point mutations and copy number variations in NLGN genes have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. Methods: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents and human induced pluripotent stem cell-derived neurons. Results: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. Limitations: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on in ASD model animals and patients. Conclusions: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.

scholarly journals Neuroligin3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function

2020 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Ming Leung ◽  
Takuya Watanabe ◽  
Amy Cheung ◽  
Masahiko Watanabe ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Splice Isoforms ◽  
Inhibitory Synaptic Transmission

ABSTRACTSynapse formation is a dynamic process essential for neuronal circuit development and maturation. At the synaptic cleft, trans-synaptic protein-protein interactions constitute major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity. Dysregulation of the E-I balance has been implicated in neurodevelopmental disorders including autism spectrum disorders. However, the molecular mechanisms underlying E-I balance remain to be elucidated. Here, we investigate Neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that Nlgn3 protein differentially regulates inhibitory synaptic transmission in a splice isoform-dependent manner at hippocampal CA1 synapses. Distinct subcellular localization patterns of Nlgn3 isoforms contribute to the functional differences observed among splice variants. Finally, single-cell sequencing analysis reveals that Nlgn1 and Nlgn3 are the major Nlgn genes and that expression of Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons.

scholarly journals Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

2019 ◽  
Vol 116 (14) ◽  
pp. 7083-7088 ◽  
Author(s):  
Min Ma ◽  
Qian Ren ◽  
Jun Yang ◽  
Kai Zhang ◽  
Zhongwei Xiong ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Autism Spectrum ◽  
Postmortem Brain ◽  
Maternal Immune Activation ◽  
Increased Activity

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (orEPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression ofEPHX2mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.

scholarly journals Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism

2021 ◽  
Vol 15 ◽  
Author(s):  
Isabel Barón-Mendoza ◽  
Emely Maqueda-Martínez ◽  
Mónica Martínez-Marcial ◽  
Marisol De la Fuente-Granada ◽  
Margarita Gómez-Chavarin ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Dendritic Spines ◽  
Metabotropic Glutamate Receptor ◽  
Inbred Mouse ◽  
Inbred Mouse Strain ◽  
Stereotyped Behavior ◽  
Autism Spectrum ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Spine Density

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.

scholarly journals JNK Signaling in Drosophila Aging and Longevity

2021 ◽  
Vol 22 (17) ◽  
pp. 9649
Author(s):  
Tian Gan ◽  
Lixia Fan ◽  
Long Zhao ◽  
Mala Misra ◽  
Min Liu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fat Body ◽  
Dependent Manner ◽  
Jnk Signaling ◽  
Specific Effects ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Organ Specific ◽  
Jnk Signaling Pathway ◽  
Stress Damage

The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases—including metabolic organs (intestine and fat body), neurons, and muscles—we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila.

scholarly journals Leptin Promotes Expression of EMT-Related Transcription Factors and Invasion in a Src and FAK-Dependent Pathway in MCF10A Mammary Epithelial Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1133 ◽  
Author(s):  
Monserrat Olea-Flores ◽  
Miriam Zuñiga-Eulogio ◽  
Arvey Tacuba-Saavedra ◽  
Magdalena Bueno-Salgado ◽  
Andrea Sánchez-Carvajal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Matrix Metalloproteases ◽  
Migration And Invasion ◽  
Mcf10a Cell ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Mcf10a Cells ◽  
Invadopodia Formation

Leptin is one of the main adipokines secreted in breast tissue. Leptin promotes epithelial–mesenchymal transition (EMT), cell migration and invasion in epithelial breast cells, leading to tumor progression. Although, the molecular mechanisms that underlie these events are not fully understood, the activation of different signaling pathways appears to be essential. In this sense, the effects of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, are not completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases’ chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT-related transcription factors Twist and β-catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the Transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that leptin promotes an increase in the expression levels of Twist and β-catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner.

Molecular Mechanisms of the Pre-TCR Alpha Chain (pTa) Enhancer Transcriptional Regulation by Notch1.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3649-3649
Author(s):  
Cedric Stevens Tremblay ◽  
Mathieu Tremblay ◽  
Sabine Herblot ◽  
Trang Hoang
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Consensus Sequence ◽  
Luciferase Reporter ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Double Negative ◽  
Enhancer Activity ◽  
E Boxes

Abstract Abstract 3649 Poster Board III-585 The Notch1 pathway and pre-TCR signalling are critical regulators of thymocyte development that have been implicated in T-cell acute lymphoblastic leukemia (T-ALL). Although the pre-TCR is required for Notch-dependent T-ALL, the role of pre-TCR alpha (pTa) as a Notch1 target remains controversial. Previous work in our laboratory has shown that the pTa gene is a target gene of the E2A-HEB transcription factors and that the SCL and LMO1 or LMO2 oncogenic transcription factors inhibits E2A activity and pTa expression, thereby causing thymocyte differentiation arrest during the pre-leukemic stage. SCL and LMO1/2 are implicated in 25% of T-ALL cases and induce aggressive T-ALL in transgenic (tg) mice when inappropriately expressed in the thymus. To define the mechanism regulating pTa expression by Notch1 and SCL, we used pTa regulatory sequences as a tool. To this end, we have performed transcriptional assays by co-delivering a luciferase reporter gene construct driven by the 200 bp pTa enhancer sequence with or without SCL or Notch1 intracellular domain (N1ICD), the functional fragment of the Notch1 receptor. Sequence analysis of the pTa enhancer revealed the presence of four E boxes that are potential binding sites for E2A-HEB and a CSL consensus sequence that can recruit the CSL/RBP-Jk transcription factor. Transcriptional assays in double negative thymomas indicated that the integrity of E box 2 and 3 (that recruit E2A-HEB) are essential for pTa enhancer activity in DN thymocytes, confirming the importance of E2A-HEB for pTa expression in these cells. In contrast, the CSL consensus sequence is important but not essential for pTa enhancer activity in these cells, consistent with previous results based on a conditional Notch1 knock out. In the presence of N1ICD, pTa enhancer sequences are strongly activated, either in fibroblasts or in double negative T cell lines in a dose dependent manner. This activation requires the integrity of the CSL consensus sequence but not of the E boxes. Moreover, we found that N1ICD strongly overrides the inhibitory activity of SCL on the pTa enhancer. Inhibition by SCL requires the integrity of E2 and E3 but not the CSL, confirming that SCL inhibits E2A-HEB activity, without affecting N1ICD. Together, our observations indicate that the regulation of pTa enhancer activity by Notch1 and E2A/HEB occur though independent mechanisms. Disclosures: No relevant conflicts of interest to declare.

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