scholarly journals FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

2016 ◽  
Vol 113 (45) ◽  
pp. E7087-E7096 ◽  
Author(s):  
Ricardo H. Paap ◽  
Saskia Oosterbroek ◽  
Cindy M. R. J. Wagemans ◽  
Lars von Oerthel ◽  
Raymond D. Schellevis ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Cortical Development ◽  
Forkhead Transcription Factor ◽  
Altered Expression ◽  
Radial Migration ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Developing Neocortex

The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6+/− and FoxO6−/− mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6. We then show that FoxO6 binds to DAF-16–binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6+/− and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.

Herpesvirus-Associated Proliferative Skin Disease in Frogs and Toads: Proposed Pathogenesis

2021 ◽  
pp. 030098582110063
Author(s):  
Francesco C. Origgi ◽  
Patricia Otten ◽  
Petra Lohmann ◽  
Ursula Sattler ◽  
Thomas Wahli ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rana Temporaria ◽  
Skin Lesions ◽  
Bufo Bufo ◽  
Careful Examination ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Cell Remodeling ◽  
Tissue Changes

A comparative study was carried out on common and agile frogs ( Rana temporaria and R. dalmatina) naturally infected with ranid herpesvirus 3 (RaHV3) and common toads ( Bufo bufo) naturally infected with bufonid herpesvirus 1 (BfHV1) to investigate common pathogenetic pathways and molecular mechanisms based on macroscopic, microscopic, and ultrastructural pathology as well as evaluation of gene expression. Careful examination of the tissue changes, supported by in situ hybridization, at different stages of development in 6 frogs and 14 toads revealed that the skin lesions are likely transient, and part of a tissue cycle necessary for viral replication in the infected hosts. Transcriptomic analysis, carried out on 2 naturally infected and 2 naïve common frogs ( Rana temporaria) and 2 naturally infected and 2 naïve common toads ( Bufo bufo), revealed altered expression of genes involved in signaling and cell remodeling in diseased animals. Finally, virus transcriptomics revealed that both RaHV3 and BfHV1 had relatively high expression of a putative immunomodulating gene predicted to encode a decoy receptor for tumor necrosis factor in the skin of the infected hosts. Thus, the comparable lesions in infected frogs and toads appear to reflect a concerted epidermal and viral cycle, with presumptive involvement of signaling and gene remodeling host and immunomodulatory viral genes.

scholarly journals AMP-activated protein kinase regulates cytoplasmic dynein behavior and contributes to neuronal migration in the developing neocortex

Development ◽  
2020 ◽  
Vol 147 (14) ◽  
pp. dev187310
Author(s):  
Yasuki Naito ◽  
Naoyuki Asada ◽  
Minh Dang Nguyen ◽  
Kamon Sanada
Keyword(s):  
Protein Kinase ◽  
Neuronal Migration ◽  
Pyramidal Neurons ◽  
Resistant Mutant ◽  
Cytoplasmic Dynein ◽  
Radial Migration ◽  
Dynein Intermediate Chain ◽  
Microtubule Motor ◽  
Developing Neocortex ◽  
Amp Activated Protein Kinase

ABSTRACTThe microtubule motor cytoplasmic dynein contributes to radial migration of newborn pyramidal neurons in the developing neocortex. Here, we show that AMP-activated protein kinase (AMPK) mediates the nucleus-centrosome coupling, a key process for radial neuronal migration that relies on dynein. Depletion of the catalytic subunit of AMPK in migrating neurons impairs this coupling as well as neuronal migration. AMPK shows overlapping subcellular distribution with cytoplasmic dynein and the two proteins interact with each other. Pharmacological inhibition or activation of AMPK modifies the phosphorylation states of dynein intermediate chain (DIC) and dynein functions. Furthermore, AMPK phosphorylates DIC at Ser81. Expression of a phospho-resistant mutant of DIC retards neuronal migration in a similar way to AMPK depletion. Conversely, expression of the phospho-mimetic mutant of DIC alleviates impaired neuronal migration caused by AMPK depletion. Thus, AMPK-regulated dynein function via Ser81 DIC phosphorylation is crucial for radial neuronal migration.

scholarly journals In utero Bisphenol A Exposure Is Linked with Sex Specific Changes in the Transcriptome and Methylome of Human Amniocytes

2019 ◽  
Vol 105 (2) ◽  
pp. 453-467
Author(s):  
Amita Bansal ◽  
Nicole Robles-Matos ◽  
Paul Zhiping Wang ◽  
David E Condon ◽  
Apoorva Joshi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bisphenol A ◽  
Gestational Age ◽  
Molecular Mechanisms ◽  
In Utero ◽  
Metabolic Dysfunction ◽  
Altered Expression ◽  
Obesity And Diabetes ◽  
Genome Wide

Abstract Context Prenatal exposure to bisphenol A (BPA) is linked to obesity and diabetes but the molecular mechanisms driving these phenomena are not known. Alterations in deoxyribonucleic acid (DNA) methylation in amniocytes exposed to BPA in utero represent a potential mechanism leading to metabolic dysfunction later in life. Objective To profile changes in genome-wide DNA methylation and expression in second trimester human amniocytes exposed to BPA in utero. Design A nested case-control study was performed in amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis, and gestational age at birth. Cases had amniotic fluid BPA measuring 0.251 to 23.74 ng/mL. Sex-specific genome-wide DNA methylation analysis and RNA-sequencing (RNA-seq) were performed to determine differentially methylated regions (DMRs) and gene expression changes associated with BPA exposure. Ingenuity pathway analysis was performed to identify biologically relevant pathways enriched after BPA exposure. In silico Hi-C analysis identified potential chromatin interactions with DMRs. Results There were 101 genes with altered expression in male amniocytes exposed to BPA (q < 0.05) in utero, with enrichment of pathways critical to hepatic dysfunction, collagen signaling and adipogenesis. Thirty-six DMRs were identified in male BPA-exposed amniocytes and 14 in female amniocyte analysis (q < 0.05). Hi-C analysis identified interactions between DMRs and 24 genes with expression changes in male amniocytes and 12 in female amniocytes (P < 0.05). Conclusion In a unique repository of human amniocytes exposed to BPA in utero, sex-specific analyses identified gene expression changes in pathways associated with metabolic disease and novel DMRs with potential distal regulatory functions.

scholarly journals Genomic analyses of early responses to radiation in glioblastoma reveal new alterations at transcription, splicing, and translation levels

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne C. Burns ◽  
Hoda Mirsafian ◽  
Wenzheng Li ◽  
Dat T. Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Post Radiation ◽  
Main Component

Abstract High-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. Changes at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. Our integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Targeting the SLIT/ROBO pathway in tumor progression: molecular mechanisms and therapeutic perspectives

2019 ◽  
Vol 11 ◽  
pp. 175883591985523 ◽  
Author(s):  
Zhengdong Jiang ◽  
Gang Liang ◽  
Ying Xiao ◽  
Tao Qin ◽  
Xin Chen ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Tumor Development ◽  
Tumor Promotion ◽  
Cancer Therapies ◽  
Malignant Cells ◽  
Robo Receptors

The SLITs (SLIT1, SLIT2, and SLIT3) are a family of secreted proteins that mediate positional interactions between cells and their environment during development by signaling through ROBO receptors (ROBO1, ROBO2, ROBO3, and ROBO4). The SLIT/ROBO signaling pathway has been shown to participate in axonal repulsion, axon guidance, and neuronal migration in the nervous system and the formation of the vascular system. However, the role of the SLIT/ROBO pathway has not been thoroughly clarified in tumor development. The SLIT/ROBO pathway can produce both beneficial and detrimental effects in the growth of malignant cells. It has been confirmed that SLIT/ROBO play contradictory roles in tumorigenesis. Here, we discuss the tumor promotion and tumor suppression roles of the SLIT/ROBO pathway in tumor growth, angiogenesis, migration, and the tumor microenvironment. Understanding these roles will help us develop more effective cancer therapies.

scholarly journals Endometritis and pyometra in bitches: a review

2013 ◽  
Vol 58 (No. 6) ◽  
pp. 289-297 ◽  
Author(s):  
B. Kempisty ◽  
D. Bukowska ◽  
M. Wozna ◽  
H. Piotrowska ◽  
M. Jackowska ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Reproductive Tract ◽  
Molecular Level ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Clinical Stages ◽  
Compound Process ◽  
Immunological Changes

Endometritis-pyometra is the most frequent and complex pathology in domestic bitches. This process involves several immunological changes as well as molecular mechanisms responsible for inflammation in the female uterus. The various clinical stages of pyometra are associated with various symptoms. In this review, several aspects are described, including physiological and pathological mechanisms as well as molecular changes which take place during induction of endometritis-pyometra. The authors also highlight the important role of growth factors and their receptors in this process. It is well known that pyometra is a compound process which mainly involves immunological changes during inflammation. However, this review presents a new overview of this process, which includes changes at the molecular level, e.g., the altered expression of genes crucial for the development of this disease. Although pyometra is the most frequent disease of the reproductive tract in bitches, the molecular basis of this process is still not entirely understood.  

scholarly journals Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate targets to improve treatment outcomes

2020 ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne Burns ◽  
Hoda Mirsafian ◽  
Whenzheng LI ◽  
Dat Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Improve Treatment ◽  
Expression Of Genes ◽  
Main Component

Abstract BackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. Methods: We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio- resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Phosphorylation of Focal Adhesion Kinase at Tyr925: Role in Glia-Dependent and Independent Migration Through Regulating Cofilin and N-Cadherin

2021 ◽  
Author(s):  
Lingzhen Song ◽  
Shanting Zhao ◽  
Michael Frotscher ◽  
Xuejun Chai
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Ventricular Zone ◽  
Focal Adhesions ◽  
Developing Neocortex ◽  
Reelin Signaling ◽  
Highly Correlated

Abstract The adult neocortex is a six-layered structure, consisting of nearly continuous layers of neurons that are generated with large temporal diversity. During development, cortical neurons originating from the ventricular zone migrate towards the Reelin-containing marginal zone in an inside-out arrangement. Focal adhesion kinase (FAK), one tyrosine kinase localizing to focal adhesions, has been shown to be activated by Src, an important downstream molecule of Reelin signaling, at tyrosine 925 (Y925). Up to date, the precise molecular mechanisms of FAK and its phosphorylation at Y925 during neuronal migration are still unclear. Combining in utero electroporation with immunohistochemistry and live imaging, we examined the function of FAK in regulating neuronal migration. We show that phosphorylated FAK is colocalized with Reelin positive cells in the developing neocortex and hippocampus. Phosphorylation of FAK at Y925 is significantly reduced in reeler mice. Overexpression and dephosphorylation of FAK impair locomotion and translocation, resulting in migration inhibition and dislocation of both late-born and early-born neurons. These migration defects are highly correlated to the function of FAK in regulating cofilin phosphorylation and N-Cadherin expression, both are involved in Reelin signaling pathway. Thus, phosphorylation of focal adhesion kinase at Y925 is crucial for both glia-dependent and independent neuronal migration.

scholarly journals Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus

2012 ◽  
Vol 44 (20) ◽  
pp. 981-991 ◽  
Author(s):  
Christopher G. Vecsey ◽  
Lucia Peixoto ◽  
Jennifer H. K. Choi ◽  
Mathieu Wimmer ◽  
Devan Jaganath ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Sleep Deprivation ◽  
Molecular Mechanisms ◽  
Brain Area ◽  
Genomic Analysis ◽  
Long Term Memory ◽  
Altered Expression ◽  
Recovery Sleep ◽  
Genome Wide ◽  
Mouse Hippocampus

Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.

scholarly journals Pasteurella multocida Gene Expression in Response to Iron Limitation

2001 ◽  
Vol 69 (6) ◽  
pp. 4109-4115 ◽  
Author(s):  
Michael L. Paustian ◽  
Barbara J. May ◽  
Vivek Kapur
Keyword(s):  
Gene Expression ◽  
Pasteurella Multocida ◽  
Molecular Mechanisms ◽  
Iron Acquisition ◽  
Expression Profiles ◽  
Growth Conditions ◽  
Whole Genome ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Wide Range

ABSTRACT Pasteurella multocida is the causative agent of a wide range of diseases in avian and mammalian hosts. Gene expression in response to low iron conditions was analyzed in P. multocida using whole-genome microarrays. The analysis shows that the expression of genes involved in energy metabolism and electron transport generally decreased 2.1- to 6-fold while that of genes used for iron binding and transport increased 2.1- to 7.7-fold in P. multocida during the first 2 h of growth under iron-limiting conditions compared with controls. Notably, 27% of the genes with significantly altered expression had no known function, illustrating the limitations of using publicly available databases to identify genes involved in microbial metabolism and pathogenesis. Taken together, the results of our investigations demonstrate the utility of whole-genome microarray analyses for the identification of genes with altered expression profiles during varying growth conditions and provide a framework for the detailed analysis of the molecular mechanisms of iron acquisition and metabolism in P. multocida and other gram-negative bacteria.

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