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      The WWOX Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells

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          Abstract

          The brain is the most functionally organized structure of all organs. It manages behavior, perception and higher cognitive functions. The WWOX gene is non-classical tumor suppressor gene, which has been shown to have an impact on proliferation, apoptosis and migration processes. Moreover, genetic aberrations in WWOX induce severe neuropathological phenotypes in humans and rodents. The aim of the present study was to investigate in detail the impact of WWOX on human neural progenitor cell (hNPC) maintenance and how depletion of WWOX disturbs signaling pathways playing a pivotal role in neuronal differentiation and central nervous system (CNS) organogenesis. hNPC with a silenced WWOX gene exhibited lowered mitochondrial redox potential, enhanced adhesion to fibronectin and extracellular matrix protein mixture, downregulation of MMP2/9 expression and impaired 3D growth. Global transcriptome analysis using cap analysis of gene expression (CAGE) found that WWOX downregulation significantly changes the expression of multiple genes engaged in cytoskeleton organization, adhesion, cell signaling and chromatin remodeling. The massive changes in gene expression caused by WWOX silencing may strongly affect the differentiation and migration of neurons in organogenesis, brain injury, cancerogenesis or neurodifferentiation. WWOX gene appears to be an important regulator of neural tissue architecture and function.

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          Most cited references64

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          The UCSC genome browser and associated tools

          The UCSC Genome Browser (http://genome.ucsc.edu) is a graphical viewer for genomic data now in its 13th year. Since the early days of the Human Genome Project, it has presented an integrated view of genomic data of many kinds. Now home to assemblies for 58 organisms, the Browser presents visualization of annotations mapped to genomic coordinates. The ability to juxtapose annotations of many types facilitates inquiry-driven data mining. Gene predictions, mRNA alignments, epigenomic data from the ENCODE project, conservation scores from vertebrate whole-genome alignments and variation data may be viewed at any scale from a single base to an entire chromosome. The Browser also includes many other widely used tools, including BLAT, which is useful for alignments from high-throughput sequencing experiments. Private data uploaded as Custom Tracks and Data Hubs in many formats may be displayed alongside the rich compendium of precomputed data in the UCSC database. The Table Browser is a full-featured graphical interface, which allows querying, filtering and intersection of data tables. The Saved Session feature allows users to store and share customized views, enhancing the utility of the system for organizing multiple trains of thought. Binary Alignment/Map (BAM), Variant Call Format and the Personal Genome Single Nucleotide Polymorphisms (SNPs) data formats are useful for visualizing a large sequencing experiment (whole-genome or whole-exome), where the differences between the data set and the reference assembly may be displayed graphically. Support for high-throughput sequencing extends to compact, indexed data formats, such as BAM, bigBed and bigWig, allowing rapid visualization of large datasets from RNA-seq and ChIP-seq experiments via local hosting.
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            Molecular mechanisms of axon guidance.

            Axons are guided along specific pathways by attractive and repulsive cues in the extracellular environment. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules, including netrins, Slits, semaphorins, and ephrins. Guidance cues steer axons by regulating cytoskeletal dynamics in the growth cone through signaling pathways that are still only poorly understood. Elaborate regulatory mechanisms ensure that a given cue elicits the right response from the right axons at the right time but is otherwise ignored. With such regulatory mechanisms in place, a relatively small number of guidance factors can be used to generate intricate patterns of neuronal wiring.
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              5' end-centered expression profiling using cap-analysis gene expression and next-generation sequencing.

              Cap-analysis gene expression (CAGE) provides accurate high-throughput measurement of RNA expression. CAGE allows mapping of all the initiation sites of both capped coding and noncoding RNAs. In addition, transcriptional start sites within promoters are characterized at single-nucleotide resolution. The latter allows the regulatory inputs driving gene expression to be studied, which in turn enables the construction of transcriptional networks. Here we provide an optimized protocol for the construction of CAGE libraries on the basis of the preparation of 27-nt-long tags corresponding to initial bases at the 5' ends of capped RNAs. We have optimized the methods using simple steps based on filtration, which altogether takes 4 d to complete. The CAGE tags can be readily sequenced with Illumina sequencers, and upon modification they are also amenable to sequencing using other platforms.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                30 August 2019
                2019
                : 13
                Affiliations
                Department of Molecular Carcinogenesis, Medical University of Łódź , Łódź, Poland
                Author notes

                Edited by: Mario Eduardo Guido, Center for Research in Biological Chemistry Córdoba (CIQUIBIC), Argentina

                Reviewed by: Gourav Roy Choudhury, University of Pennsylvania, United States; Silvina Varónica Sonzogni, University of Buenos Aires, Argentina

                *Correspondence: Katarzyna Kośla, katarzyna.kosla@ 123456umed.lodz.pl

                This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2019.00391
                6730490
                be8c5e86-ee86-4e39-89ab-97732e527b85
                Copyright © 2019 Kośla, Płuciennik, Styczeń-Binkowska, Nowakowska, Orzechowska and Bednarek.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 11, Tables: 1, Equations: 0, References: 68, Pages: 13, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences
                wwox,neural progenitor cells,neuronal differentiation,neurodegeneration,woree,scar,cage
                Neurosciences
                wwox, neural progenitor cells, neuronal differentiation, neurodegeneration, woree, scar, cage

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