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Genetic engineering AND neuron

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https://www.readbyqxmd.com/read/27874828/sf-1-expression-in-the-hypothalamus-is-required-for-beneficial-metabolic-effects-of-exercise
#1
Teppei Fujikawa, Carlos M Castorena, Mackenzie Pearson, Christine M Kusminski, Newaz Ahmed, Pavan K Battiprolu, Ki Woo Kim, Syann Lee, Joseph A Hill, Philipp E Scherer, William L Holland, Joel K Elmquist
Exercise has numerous beneficial metabolic effects. The central nervous system (CNS) is critical for regulating energy balance and coordinating whole body metabolism. However, a role for the CNS in the regulation of metabolism in the context of the exercise remains less clear. Here, using genetically engineered mice we assessed the requirement of steroidogenic factor-1 (SF-1) expression in neurons of the ventromedial hypothalamic nucleus (VMH) in mediating the beneficial effects of exercise on metabolism. We found that VMH-specific deletion of SF-1 blunts (a) the reductions in fat mass, (b) improvements in glycemia, and (c) increases in energy expenditure that are associated with exercise training...
November 22, 2016: ELife
https://www.readbyqxmd.com/read/27867348/better-targeting-better-efficiency-for-wide-scale-neuronal-transduction-with-the-synapsin-promoter-and-aav-php-b
#2
Kasey L Jackson, Robert D Dayton, Benjamin E Deverman, Ronald L Klein
Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27851729/in-vivo-genome-editing-via-crispr-cas9-mediated-homology-independent-targeted-integration
#3
Keiichiro Suzuki, Yuji Tsunekawa, Reyna Hernandez-Benitez, Jun Wu, Jie Zhu, Euiseok J Kim, Fumiyuki Hatanaka, Mako Yamamoto, Toshikazu Araoka, Zhe Li, Masakazu Kurita, Tomoaki Hishida, Mo Li, Emi Aizawa, Shicheng Guo, Song Chen, April Goebl, Rupa Devi Soligalla, Jing Qu, Tingshuai Jiang, Xin Fu, Maryam Jafari, Concepcion Rodriguez Esteban, W Travis Berggren, Jeronimo Lajara, Estrella Nuñez-Delicado, Pedro Guillen, Josep M Campistol, Fumio Matsuzaki, Guang-Hui Liu, Pierre Magistretti, Kun Zhang, Edward M Callaway, Kang Zhang, Juan Carlos Izpisua Belmonte
Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals)...
December 1, 2016: Nature
https://www.readbyqxmd.com/read/27833556/increased-motor-impairing-effects-of-the-neuroactive-steroid-pregnanolone-in-mice-with-targeted-inactivation-of-the-gabaa-receptor-%C3%AE-2-subunit-in-the-cerebellum
#4
Elli Leppä, Anni-Maija Linden, Maria I Aller, Peer Wulff, Olga Vekovischeva, Bernhard Luscher, Hartmut Lüddens, William Wisden, Esa R Korpi
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27822501/inhibition-of-ikk%C3%AE-reduces-ethanol-consumption-in-c57bl-6j-mice
#5
Jay M Truitt, Yuri A Blednov, Jillian M Benavidez, Mendy Black, Olga Ponomareva, Jade Law, Morgan Merriman, Sami Horani, Kelly Jameson, Amy W Lasek, R Adron Harris, R Dayne Mayfield
Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated...
September 2016: ENeuro
https://www.readbyqxmd.com/read/27816769/in-vivocharacterization-of-the-aspartyl-trna-synthetase-dars-homing-in-on-the-leukodystrophy-hbsl
#6
Dominik Fröhlich, Alexandra K Suchowerska, Ziggy H T Spencer, Georg von Jonquieres, Claudia B Klugmann, Andre Bongers, Fabien Delerue, Holly Stefen, Lars M Ittner, Thomas Fath, Gary D Housley, Matthias Klugmann
BACKGROUND: The recently diagnosed leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is caused by mutations of the cytoplasmic aspartyl-tRNA synthetase geneDARS. The physiological role of DARS in translation is to accurately pair aspartate with its cognate tRNA. Clinically, HBSL subjects show a distinct pattern of hypomyelination and develop progressive leg spasticity, variable cognitive impairment and epilepsy. To elucidate the underlying pathomechanism, we comprehensively assessed endogenous DARS expression in mice...
November 2, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27802273/fusion-of-human-fetal-mesenchymal-stem-cells-with-degenerating-cerebellar-neurons-in-spinocerebellar-ataxia-type-1-model-mice
#7
Fathul Huda, Yiping Fan, Mamiko Suzuki, Ayumu Konno, Yasunori Matsuzaki, Nobutaka Takahashi, Jerry K Y Chan, Hirokazu Hirai
Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event...
2016: PloS One
https://www.readbyqxmd.com/read/27775718/correcting-mitochondrial-fusion-by-manipulating-mitofusin-conformations
#8
Antonietta Franco, Richard N Kitsis, Julie A Fleischer, Evripidis Gavathiotis, Opher S Kornfeld, Guohua Gong, Nikolaos Biris, Ann Benz, Nir Qvit, Sara K Donnelly, Yun Chen, Steven Mennerick, Louis Hodgson, Daria Mochly-Rosen, Gerald W Dorn Ii
Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is not completely understood. Here we show that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions...
December 1, 2016: Nature
https://www.readbyqxmd.com/read/27725685/generation-of-transgenic-marmosets-expressing-genetically-encoded-calcium-indicators
#9
Jung Eun Park, Xian Feng Zhang, Sang-Ho Choi, Junko Okahara, Erika Sasaki, Afonso C Silva
Chronic monitoring of neuronal activity in the living brain with optical imaging techniques became feasible owing to the continued development of genetically encoded calcium indicators (GECIs). Here we report for the first time the successful generation of transgenic marmosets (Callithrix jacchus), an important nonhuman primate model in neurophysiological research, which were engineered to express the green fluorescent protein (GFP)-based family of GECIs, GCaMP, under control of either the CMV or the hSyn promoter...
October 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27699601/generation-of-a-functional-human-neural-network-by-ndm29-overexpression-in-neuroblastoma-cancer-cells
#10
Susanna Alloisio, Patrizia Garbati, Federica Viti, Silvia Dante, Raffaella Barbieri, Giovanni Arnaldi, Alessia Petrelli, Arianna Gigoni, Paolo Giannoni, Rodolfo Quarto, Mario Nobile, Massimo Vassalli, Aldo Pagano
Recent advances in life sciences suggest that human and rodent cell responses to stimuli might differ significantly. In this context, the results achieved in neurotoxicology and biomedical research practices using neural networks obtained from mouse or rat primary culture of neurons would benefit of the parallel evaluation of the same parameters using fully differentiated neurons with a human genetic background, thus emphasizing the current need of neuronal cells with human origin. In this work, we developed a human functionally active neural network derived by human neuroblastoma cancer cells genetically engineered to overexpress NDM29, a non-coding RNA whose increased synthesis causes the differentiation toward a neuronal phenotype...
October 3, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27693255/molecular-and-neural-functions-of-rai1-the-causal-gene-for-smith-magenis-syndrome
#11
Wei-Hsiang Huang, Casey J Guenthner, Jin Xu, Tiffany Nguyen, Lindsay A Schwarz, Alex W Wilkinson, Or Gozani, Howard Y Chang, Mehrdad Shamloo, Liqun Luo
Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication...
October 19, 2016: Neuron
https://www.readbyqxmd.com/read/27683896/genetically-encoded-voltage-indicators-opportunities-and-challenges
#12
Helen H Yang, François St-Pierre
UNLABELLED: A longstanding goal in neuroscience is to understand how spatiotemporal patterns of neuronal electrical activity underlie brain function, from sensory representations to decision making. An emerging technology for monitoring electrical dynamics, voltage imaging using genetically encoded voltage indicators (GEVIs), couples the power of genetics with the advantages of light. Here, we review the properties that determine indicator performance and applicability, discussing both recent progress and technical limitations...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27677952/a-new-design-for-a-green-calcium-indicator-with-a-smaller-size-and-a-reduced-number-of-calcium-binding-sites
#13
Natalia V Barykina, Oksana M Subach, Danila A Doronin, Vladimir P Sotskov, Marina A Roshchina, Tatiana A Kunitsyna, Aleksey Y Malyshev, Ivan V Smirnov, Asya M Azieva, Ilya S Sokolov, Kiryl D Piatkevich, Mikhail S Burtsev, Anna M Varizhuk, Galina E Pozmogova, Konstantin V Anokhin, Fedor V Subach, Grigori N Enikolopov
Genetically encoded calcium indicators (GECIs) are mainly represented by two- or one-fluorophore-based sensors. One type of two-fluorophore-based sensor, carrying Opsanus troponin C (TnC) as the Ca(2+)-binding moiety, has two binding sites for calcium ions, providing a linear response to calcium ions. One-fluorophore-based sensors have four Ca(2+)-binding sites but are better suited for in vivo experiments. Herein, we describe a novel design for a one-fluorophore-based GECI with two Ca(2+)-binding sites. The engineered sensor, called NTnC, uses TnC as the Ca(2+)-binding moiety, inserted in the mNeonGreen fluorescent protein...
September 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27662371/analysis-of-genome-wide-monoallelic-expression-patterns-in-three-major-cell-types-of-mouse-visual-cortex-using-laser-capture-microdissection
#14
Chia-Yi Lin, Shih-Chuan Huang, Chun-Che Tung, Chih-Hsuan Chou, Susan Shur-Fen Gau, Hsien-Sung Huang
Genomic imprinting is an epigenetic mechanism causing monoallelic expression in a parent-of-origin-specific manner. Disruption of imprinted genes causes various neurological and psychiatric disorders. However, the role of imprinted genes in the brain is largely unknown. Different cell types within distinct brain regions can influence the genomic imprinting status, but imprinted genes in single cell types within distinct brain regions have not been characterized on a genome-wide scale. To address this critical question, we used a multi-stage approach, which combined genetically engineered mice with fluorescence-based laser capture microdissection (LCM) to capture excitatory neurons, inhibitory neurons and astrocytes as single cells in layer 2/3 of mouse visual cortex...
2016: PloS One
https://www.readbyqxmd.com/read/27660327/monitoring-cell-cell-contacts-in-vivo-in-transgenic-animals
#15
Ting-Hao Huang, Tarciso Velho, Carlos Lois
We used a synthetic genetic system based on ligand-induced intramembrane proteolysis to monitor cell-cell contacts in animals. Upon ligand-receptor interaction in sites of cell-cell contact, the transmembrane domain of an engineered receptor is cleaved by intramembrane proteolysis and releases a protein fragment that regulates transcription in the interacting partners. We demonstrate that the system can be used to regulate gene expression between interacting cells both in vitro and in vivo, in transgenic Drosophila We show that the system allows for detection of interactions between neurons and glia in the Drosophila nervous system...
September 22, 2016: Development
https://www.readbyqxmd.com/read/27622154/selected-suitable-seed-cell-scaffold-and-growth-factor-could-maximize-the-repair-effect-using-tissue-engineering-method-in-spinal-cord-injury
#16
REVIEW
Wen-Chen Ji, Xiao-Wei Zhang, Yu-Sheng Qiu
Spinal cord injury usually leads to permanent disability, which could cause a huge financial problem to the patient. Up to now there is no effective method to treat this disease. The key of the treatment is to enable the damage zone axonal regeneration and luckily it could go through the damage zone; last a connection can be established with the target neurons. This study attempts to combine stem cell, material science and genetic modification technology together, by preparing two genes modified adipose-derived stem cells and inducing them into neuron direction; then by compositing them on the silk fibroin/chitosan scaffold and implanting them into the spinal cord injury model, seed cells can have features of neuron cells...
August 20, 2016: World Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27617177/minor-differences-in-the-molecular-machinery-mediating-regulated-membrane-fusion-has-major-impact-on-metabolic-health
#17
Ismael Valladolid-Acebes, Teresa Daraio, Kerstin Brismar, Tomas Hökfelt, Christina Bark
The exocytosis of signaling molecules from neuronal, neuroendocrine and endocrine cells is regulated by membrane fusion involving SNAP-25 and associated SNARE proteins. The importance of this process for metabolic control recently became evident by studies of mouse mutants genetically engineered to only express one of 2 closely related, alternatively-spliced variants of SNAP-25. The results showed that even minor differences in the function of proteins regulating exocytosis are sufficient to provoke metabolic disease, including hyperglycaemia, liver steatosis, adipocyte hypertrophy and obesity...
July 2016: Adipocyte
https://www.readbyqxmd.com/read/27611437/ivermectin-activated-cation-permeable-glycine-receptors-for-the-chemogenetic-control-of-neuronal-excitation
#18
Robiul Islam, Angelo Keramidas, Li Xu, Nela Durisic, Pankaj Sah, Joseph W Lynch
The ability to control neuronal activation is rapidly advancing our understanding of brain function and is widely viewed as having eventual therapeutic application. Although several highly effective optogenetic, optochemical genetic, and chemogenetic techniques have been developed for this purpose, new approaches may provide better solutions for addressing particular questions and would increase the number of neuronal populations that can be controlled independently. An early chemogenetic neuronal silencing method employed a glutamate receptor Cl(-) channel engineered for activation by 1-3 nM ivermectin...
September 27, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27566602/revisiting-rodent-models-octodon-degus-as-alzheimer-s-disease-model
#19
Johannes Steffen, Markus Krohn, Kristin Paarmann, Christina Schwitlick, Thomas Brüning, Rita Marreiros, Andreas Müller-Schiffmann, Carsten Korth, Katharina Braun, Jens Pahnke
Alzheimer's disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these 'engineered' models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases...
2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27491309/tyrosine-hydroxylase-th-its-cofactor-tetrahydrobiopterin-bh4-other-catecholamine-related-enzymes-and-their-human-genes-in-relation-to-the-drug-and-gene-therapies-of-parkinson-s-disease-pd-historical-overview-and-future-prospects
#20
Toshiharu Nagatsu, Ikuko Nagatsu
Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic L-amino acid decarboxylase (AADC); dopamine β-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD...
November 2016: Journal of Neural Transmission
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