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https://www.readbyqxmd.com/read/28646272/rhesus-cochlear-and-vestibular-functions-are-preserved-after-inner-ear-injection-of-saline-volume-sufficient-for-gene-therapy-delivery
#1
Chenkai Dai, Mohamed Lehar, Daniel Q Sun, Lani Swarthout Rvt, John P Carey, Tim MacLachlan, Doug Brough, Hinrich Staecker, Alexandra M Della Santina, Timothy E Hullar, Charles C Della Santina
Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome...
June 23, 2017: Journal of the Association for Research in Otolaryngology: JARO
https://www.readbyqxmd.com/read/28576729/afferent-synaptogenesis-between-ectopic-hair-cell-like-cells-and-neurites-of-spiral-ganglion-induced-by-atoh1-in-mammals-in-vitro
#2
Wen-Wei Luo, Rui Ma, Xiang Cheng, Xiao-Yu Yang, Zhao Han, Dong-Dong Ren, Ping Chen, Fang-Lu Chi, Juan-Mei Yang
Newly formed ectopic hair-cell-like cells (EHCLCs) induced by overexpression of atonal homolog 1 (Atoh1) in vitro were found to possess features of endogenous hair cells (HCs) in previous reports and in the present study. However, limited information is available regarding whether EHCLCs and native spiral ganglion neurons (SGNs) form afferent synapses, which are important for the restoration of hearing. In the current study, we focused on the afferent synaptogenesis between EHCLCs and SGN-derived dendrites...
May 31, 2017: Neuroscience
https://www.readbyqxmd.com/read/28532435/early-growth-response-protein-1-regulates-promoter-activity-of-%C3%AE-plasma-membrane-calcium-atpase-2-a-major-calcium-pump-in-the-brain-and-auditory-system
#3
Rebecca R Minich, Jin Li, Bruce L Tempel
BACKGROUND: Along with sodium/calcium (Ca(2+)) exchangers, plasma membrane Ca(2+) ATPases (ATP2Bs) are main regulators of intracellular Ca(2+) levels. There are four ATP2B paralogs encoded by four different genes. Atp2b2 encodes the protein pump with the fastest activation, ATP2B2. In mice, the Atp2b2 transcript has several alternate transcriptional start site variants: α, β, µ and δ. These variants are expressed in developmental and tissue specific manners. The α and β Atp2b2 transcripts are equally expressed in the brain...
May 22, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28512245/merkel-cell-polyomavirus-small-t-antigen-initiates-merkel-cell-carcinoma-like-tumor-development-in-mice
#4
Monique E Verhaegen, Doris Mangelberger, Paul W Harms, Markus Eberl, Dawn M Wilbert, Julia Meireles, Christopher K Bichakjian, Thomas L Saunders, Sunny Y Wong, Andrzej A Dlugosz
Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28512198/novel-role-of-rac-mid1-signaling-in-medial-cerebellar-development
#5
Takashi Nakamura, Takehiko Ueyama, Yuzuru Ninoyu, Hirofumi Sakaguchi, Narantsog Choijookhuu, Yoshitaka Hishikawa, Hiroshi Kiyonari, Masaaki Kohta, Mizuho Sakahara, Ivan de Curtis, Eiji Kohmura, Yasuo Hisa, Atsu Aiba, Naoaki Saito
Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) mice at P8...
May 15, 2017: Development
https://www.readbyqxmd.com/read/28498550/hbx-protein-mediated-atoh1-downregulation-suppresses-arid2-expression-and-promotes-hepatocellular-carcinoma
#6
Qingzhu Gao, Kai Wang, Ke Chen, Li Liang, Yaqiu Zheng, Yunzhi Zhang, Jin Xiang, Ni Tang
Hepatitis B virus X protein plays a crucial role in the pathogenesis of hepatocellular carcinoma. We previously showed that the tumor suppressor ARID2 inhibits hepatoma cell cycle progression and tumor growth. Here, we evaluated whether hepatitis B virus X protein was involved in the modulation of ARID2 expression and hepatocarcinogenesis associated with hepatitis B virus infection. ARID2 expression was downregulated in HBV-replicative hepatoma cells, HBV transgenic mice, and HBV-related clinical HCC tissues...
May 12, 2017: Cancer Science
https://www.readbyqxmd.com/read/28490517/atoh1-promotes-leptomeningeal-dissemination-and-metastasis-of-sonic-hedgehog-subgroup-medulloblastomas
#7
Katie B Grausam, Samuel Dr Dooyema, Laure Bihannic, Hasitha Premathilake, A Sorana Morrissy, Antoine Forget, Amanda M Schaefer, Justin H Gundelach, Slobodan Macura, Diane M Maher, Xin Wang, Alex H Heglin, Xijin Ge, Erliang Zeng, Stephanie Puget, Indra Chandrasekar, Kameswaran Surendran, Richard J Bram, Ulrich Schüller, Michael D Taylor, Olivier Ayrault, Haotian Zhao
Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the Notch pathway transcription factor ATOH1, which is present in aggressive MB subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional Atoh1 mouse mutants crossed to Ptch1(+/-) mice which develop SHH-driven MB[63], animals with Atoh1 transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB...
May 10, 2017: Cancer Research
https://www.readbyqxmd.com/read/28459451/generation-of-inner-ear-organoids-containing-functional-hair-cells-from-human-pluripotent-stem-cells
#8
Karl R Koehler, Jing Nie, Emma Longworth-Mills, Xiao-Ping Liu, Jiyoon Lee, Jeffrey R Holt, Eri Hashino
The derivation of human inner ear tissue from pluripotent stem cells would enable in vitro screening of drug candidates for the treatment of hearing and balance dysfunction and may provide a source of cells for cell-based therapies of the inner ear. Here we report a method for differentiating human pluripotent stem cells to inner ear organoids that harbor functional hair cells. Using a three-dimensional culture system, we modulate TGF, BMP, FGF, and WNT signaling to generate multiple otic-vesicle-like structures from a single stem-cell aggregate...
June 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28450830/spiral-ganglion-neuron-projection-development-to-the-hindbrain-in-mice-lacking-peripheral-and-or-central-target-differentiation
#9
Karen L Elliott, Jennifer Kersigo, Ning Pan, Israt Jahan, Bernd Fritzsch
We investigate the importance of the degree of peripheral or central target differentiation for mouse auditory afferent navigation to the organ of Corti and auditory nuclei in three different mouse models: first, a mouse in which the differentiation of hair cells, but not central auditory nuclei neurons is compromised (Atoh1-cre; Atoh1(f/f) ); second, a mouse in which hair cell defects are combined with a delayed defect in central auditory nuclei neurons (Pax2-cre; Atoh1(f/f) ), and third, a mouse in which both hair cells and central auditory nuclei are absent (Atoh1(-/-))...
2017: Frontiers in Neural Circuits
https://www.readbyqxmd.com/read/28402854/in%C3%A2-vivo-interplay-between-p27-kip1-gata3-atoh1-and-pou4f3-converts-non-sensory-cells-to-hair-cells-in-adult-mice
#10
Bradley J Walters, Emily Coak, Jennifer Dearman, Grace Bailey, Tetsuji Yamashita, Bryan Kuo, Jian Zuo
Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27(Kip1) deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27(Kip1) deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age...
April 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28393066/signaling-and-transcription-factors-during-inner-ear-development-the-generation-of-hair-cells-and-otic-neurons
#11
Héctor Gálvez, Gina Abelló, Fernando Giraldez
Integration between cell signals and bHLH transcription factors plays a prominent role during the development of hair cells of the inner ear. Hair cells are the sensory receptors of the inner ear, responsible for the mechano-transduction of sound waves into electrical signals. They derive from multipotent progenitors that reside in the otic placode. Progenitor commitment is the result of cell signaling from the surrounding tissues that result in the restricted expression of SoxB1 transcription factors, Sox2 and Sox3...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28340519/barrington-s-nucleus-neuroanatomic-landscape-of-the-mouse-pontine-micturition-center
#12
Anne M J Verstegen, Veronique Vanderhorst, Paul A Gray, Mark L Zeidel, Joel C Geerling
Barrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the "pontine micturition center." Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium-sized Bar neurons located medial to the locus coeruleus (LC). Bar neurons express a GFP reporter for Vglut2, develop from a Math1/Atoh1 lineage, and exhibit immunoreactivity for NeuN...
July 1, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28323899/lawsonia-intracellularis-exploits-%C3%AE-catenin-wnt-and-notch-signalling-pathways-during-infection-of-intestinal-crypt-to-alter-cell-homeostasis-and-promote-cell-proliferation
#13
Yang W Huan, Rebecca J Bengtsson, Neil MacIntyre, Jack Guthrie, Heather Finlayson, Sionagh H Smith, Alan L Archibald, Tahar Ait-Ali
Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification...
2017: PloS One
https://www.readbyqxmd.com/read/28304405/the-erbb3-receptor-tyrosine-kinase-negatively-regulates-paneth-cells-by-pi3k-dependent-suppression-of-atoh1
#14
Dana Almohazey, Yuan-Hung Lo, Claire V Vossler, Alan J Simmons, Jonathan J Hsieh, Edie B Bucar, Michael A Schumacher, Kathryn E Hamilton, Ken S Lau, Noah F Shroyer, Mark R Frey
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche...
May 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28263708/supporting-cells-remove-and-replace-sensory-receptor-hair-cells-in-a-balance-organ-of-adult-mice
#15
Stephanie A Bucks, Brandon C Cox, Brittany A Vlosich, James P Manning, Tot B Nguyen, Jennifer S Stone
Vestibular hair cells in the inner ear encode head movements and mediate the sense of balance. These cells undergo cell death and replacement (turnover) throughout life in non-mammalian vertebrates. However, there is no definitive evidence that this process occurs in mammals. We used fate-mapping and other methods to demonstrate that utricular type II vestibular hair cells undergo turnover in adult mice under normal conditions. We found that supporting cells phagocytose both type I and II hair cells. Plp1-CreER(T2)-expressing supporting cells replace type II hair cells...
March 6, 2017: ELife
https://www.readbyqxmd.com/read/28184337/atoh1-as-a-coordinator-of-sensory-hair-cell-development-and-regeneration-in-the-cochlea
#16
Sungsu Lee, Han-Seong Jeong, Hyong-Ho Cho
Cochlear sensory hair cells (HCs) are crucial for hearing as mechanoreceptors of the auditory systems. Clarification of transcriptional regulation for the cochlear sensory HC development is crucial for the improvement of cell replacement therapies for hearing loss. Transcription factor Atoh1 is the key player during HC development and regeneration. In this review, we will focus on Atoh1 and its related signaling pathways (Notch, fibroblast growth factor, and Wnt/β-catenin signaling) involved in the development of cochlear sensory HCs...
January 2017: Chonnam Medical Journal
https://www.readbyqxmd.com/read/28174757/transcriptional-regulation-by-atoh1-and-its-target-spdef-in%C3%A2-the%C3%A2-intestine
#17
Yuan-Hung Lo, Eunah Chung, Zhaohui Li, Ying-Wooi Wan, Maxime M Mahe, Min-Shan Chen, Taeko K Noah, Kristin N Bell, Hari Krishna Yalamanchili, Tiemo J Klisch, Zhandong Liu, Joo-Seop Park, Noah F Shroyer
BACKGROUND & AIMS: The transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28086833/delta-like-4-notch-signaling-promotes-apc-min-tumor-initiation-through-angiogenic-and-non-angiogenic-related-mechanisms
#18
Marina Badenes, Alexandre Trindade, Hugo Pissarra, Luís Lopes-da-Costa, António Duarte
BACKGROUND: Delta like 4 (Dll4)/Notch signaling is a key regulator of tumor angiogenesis. Additionally, the role of Dll4 has been studied on tumor stem cells. However, as these cells are implicated in tumor angiogenesis, it is conceivable that the effect of Dll4 on these cells may be a consequence of its angiogenic function. Our aim was to evaluate the expression and dissect the functions of Dll4 in the Apc (Min/+) model of colorectal cancer. METHODS: We evaluated the protein expression pattern of Dll4 and other Notch members in the Apc (Min/+) tumors relatively to the normal gut and compared endothelial-specific with ubiquitous Dll4 knockout mice on an Apc (Min/+) background...
January 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28052248/hox2-genes-are-required-for-tonotopic-map-precision-and-sound-discrimination-in-the-mouse-auditory-brainstem
#19
Kajari Karmakar, Yuichi Narita, Jonathan Fadok, Sebastien Ducret, Alberto Loche, Taro Kitazawa, Christel Genoud, Thomas Di Meglio, Raphael Thierry, Joao Bacelo, Andreas Lüthi, Filippo M Rijli
Tonotopy is a hallmark of auditory pathways and provides the basis for sound discrimination. Little is known about the involvement of transcription factors in brainstem cochlear neurons orchestrating the tonotopic precision of pre-synaptic input. We found that in the absence of Hoxa2 and Hoxb2 function in Atoh1-derived glutamatergic bushy cells of the anterior ventral cochlear nucleus, broad input topography and sound transmission were largely preserved. However, fine-scale synaptic refinement and sharpening of isofrequency bands of cochlear neuron activation upon pure tone stimulation were impaired in Hox2 mutants, resulting in defective sound-frequency discrimination in behavioral tests...
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28044390/systematic-in-vitro-and-in-vivo-characterization-of-leukemia-inhibiting-factor-and-fibroblast-growth-factor-derived-porcine-induced-pluripotent-stem-cells
#20
Jan O Secher, Ahmet Ceylan, Gianluca Mazzoni, Kaveh Mashayekhi, Tong Li, Suchitra Muenthaisong, Troels T Nielsen, Dong Li, Shengting Li, Stoyan Petkov, Susanna Cirera, Yonglun Luo, Lori Thombs, Haja N Kadarmideen, Andras Dinnyes, Lars Bolund, Bernard A J Roelen, Mette Schmidt, Henrik Callesen, Poul Hyttel, Kristine K Freude
Derivation and stable maintenance of porcine induced pluripotent stem cells (piPSCs) is challenging. We herein systematically analyzed two piPSC lines, derived by lentiviral transduction and cultured under either leukemia inhibitory factor (LIF) or fibroblast growth factor (FGF) conditions, to shed more light on the underlying biological mechanisms of porcine pluripotency. LIF-derived piPSCs were more successful than their FGF-derived counterparts in the generation of in vitro chimeras and in teratoma formation...
January 3, 2017: Molecular Reproduction and Development
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