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Jonathan C Niclis, Carlos W Gantner, Walaa F Alsanie, Stuart J McDougall, Chris R Bye, Andrew G Elefanty, Edouard G Stanley, John M Haynes, Colin W Pouton, Lachlan H Thompson, Clare L Parish
: : Recent studies have shown evidence for the functional integration of human pluripotent stem cell (hPSC)-derived ventral midbrain dopamine (vmDA) neurons in animal models of Parkinson's disease. Although these cells present a sustainable alternative to fetal mesencephalic grafts, a number of hurdles require attention prior to clinical translation. These include the persistent use of xenogeneic reagents and challenges associated with scalability and storage of differentiated cells. In this study, we describe the first fully defined feeder- and xenogeneic-free protocol for the generation of vmDA neurons from hPSCs and utilize two novel reporter knock-in lines (LMX1A-eGFP and PITX3-eGFP) for in-depth in vitro and in vivo tracking...
October 14, 2016: Stem Cells Translational Medicine
Eric O Williams, Amy K Taylor, Eric L Bell, Rachelle Lim, Daniel M Kim, Leonard Guarente
The enhancer landscape is dramatically restructured as naive preimplantation epiblasts transition to the post-implantation state of primed pluripotency. A key factor in this process is Otx2, which is upregulated during the early stages of this transition and ultimately recruits Oct4 to a different set of enhancers. In this study, we discover that the acetylation status of Oct4 regulates the induction of the primed pluripotency gene network. Maintenance of the naive state requires the NAD-dependent deacetylase, SirT1, which deacetylates Oct4...
October 11, 2016: Cell Reports
Thibaud Mathis, Michael Housset, Chiara Eandi, Fanny Beguier, Sara Touhami, Sacha Reichman, Sebastien Augustin, Pauline Gondouin, José-Alain Sahel, Laurent Kodjikian, Olivier Goureau, Xavier Guillonneau, Florian Sennlaub
Orthodenticle homeobox 2 (OTX2) controls essential, homeostatic retinal pigment epithelial (RPE) genes in the adult. Using cocultures of human CD14(+) blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human-induced pluripotent stem cell-derived RPE cells, we show that activated Mos markedly inhibit RPEOTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF-α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others...
September 22, 2016: Aging Cell
Ben Steventon, Roberto Mayor, Andrea Streit
Cranial placodes contribute to sensory structures including the inner ear, the lens and olfactory epithelium and the neurons of the cranial sensory ganglia. At neurula stages, placode precursors are interspersed in the ectoderm surrounding the anterior neural plate before segregating into distinct placodes by as yet unknown mechanisms. Here, we perform live imaging to follow placode progenitors as they aggregate to form the lens and otic placodes. We find that while placode progenitors move with the same speed as their non-placodal neighbours, they exhibit increased persistence and directionality and these properties are required to assemble morphological placodes...
September 22, 2016: Biology Open
Ian C Tobias, Courtney R Brooks, Jonathan H Teichroeb, Daniel A Villagómez, David A Hess, Cheryle A Séguin, Dean H Betts
Naïve and primed pluripotent stem cells (PSCs) reflect discrete pluripotent states that approximate the inner cell mass or the progressively lineage-restricted perigastrulation epiblast, respectively. Cells that occupy primed pluripotency have distinct epigenetic landscapes, transcriptional circuitry, and trophic requirements compared with their naïve counterparts. The existence of multiple pluripotent states has not been explored in dogs, which show promise as outbred biomedical models with more than 300 inherited diseases that also afflict humans...
August 15, 2016: Stem Cells and Development
Xénia Latypova, Sylvain Bordereau, Alice Bleriot, Olivier Pichon, Damien Poulain, Annaïg Briand, Cédric Le Caignec, Bertrand Isidor
Mutations in OTX2 are mostly identified in patients with anophthalmia/microphthalmia with variable severity. The OTX2 homeobox gene plays a crucial role in craniofacial morphogenesis during early embryo development. We report for the first time a patient with a mandibular dysostosis caused by a 120 kb deletion including the entire coding sequence of OTX2, identified by array CGH. No ocular malformations were identified after extended ophthalmologic examination. Our data refine the clinical spectrum associated with OTX2 mutations and suggests that OTX2 haploinsufficiency should be considered as a possible cause for isolated mandibular dysostosis...
September 2016: American Journal of Medical Genetics. Part A
Miklós Sárvári, Imre Kalló, Erik Hrabovszky, Norbert Solymosi, Annie Rodolosse, Zsolt Liposits
Estradiol (E2) robustly activates transcription of a broad array of genes in the hippocampal formation of middle-aged ovariectomized rats via estrogen receptors (ERα, ERβ, and G protein-coupled ER). Selective ERβ agonists also influence hippocampal functions, although their downstream molecular targets and mechanisms are not known. In this study, we explored the effects of long-term treatment with ERβ agonist diarylpropionitrile (DPN, 0.05 mg/kg/day, sc.) on the hippocampal transcriptome in ovariectomized, middle-aged (13 month) rats...
2016: Frontiers in Cellular Neuroscience
Hoon Dong Kim, Sun Young Jang, Si Hyung Lee, Young Shin Kim, Young-Hoon Ohn, Ralf Brinkmann, Tae Kwann Park
PURPOSE: To investigate the characteristics of retinal pigment epithelium (RPE) and retinal damage induced by selective retina therapy (SRT) in mice, and to elucidate longitudinal changes in RPE cells. METHODS: C57BL/6J mice received SRT and continuous-wave laser photocoagulation (cwPC). The cell death pattern was evaluated using TUNEL assay, and proliferative potential of the RPE cells was evaluated using 5-ethynyl-2'-dexoyuridine (EdU) assay. To investigate the cell-cell integrity of RPE cells, β-catenin staining was performed...
June 1, 2016: Investigative Ophthalmology & Visual Science
Aya Shimada, Masaki Takagi, Yuka Nagashima, Kentaro Miyai, Yukihiro Hasegawa
BACKGROUND: Mutations in OTX2 cause hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency (CPHD), which are commonly detected in association with severe eye abnormalities, including anophthalmia or microphthalmia. Pituitary phenotypes of OTX2 mutation carriers are highly variable; however, ACTH deficiency during the neonatal period is not common in previous reports. OBJECTIVE: We report a novel missense OTX2 (R89P) mutation in a CPHD patient with severe hypoglycemia in the neonatal period due to ACTH deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery (ICA)...
2016: Hormone Research in Pædiatrics
Swapna Asuthkar, Maheedhara R Guda, Sarah E Martin, Reuben Antony, Karen Fernandez, Julian Lin, Andrew J Tsung, Kiran K Velpula
Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus...
August 19, 2016: Biochemical and Biophysical Research Communications
Dario Acampora, Daniela Omodei, Giuseppe Petrosino, Arcomaria Garofalo, Marco Savarese, Vincenzo Nigro, Luca Giovanni Di Giovannantonio, Vincenzo Mercadante, Antonio Simeone
Mouse embryonic stem cells (ESCs) and the inner cell mass (ICM)-derived epiblast exhibit naive pluripotency. ESC-derived epiblast stem cells (EpiSCs) and the postimplantation epiblast exhibit primed pluripotency. Although core pluripotency factors are well-characterized, additional regulators, including Otx2, recently have been shown to function during the transition from naive to primed pluripotency. Here we uncover a role for Otx2 in the control of the naive pluripotent state. We analyzed Otx2-binding activity in ESCs and EpiSCs and identified Nanog, Oct4, and Sox2 as direct targets...
June 21, 2016: Cell Reports
Hisato Kondoh, Shinji Takada, Tatsuya Takemoto
The transcription factor gene Sox2, centrally involved in neural primordial regulation, is activated by many enhancers. During the early stages of embryonic development, Sox2 is regulated by the enhancers N2 and N1 in the anterior neural plate (ANP) and posterior neural plate (PNP), respectively. This differential use of the enhancers reflects distinct regulatory mechanisms underlying the genesis of ANP and PNP. The ANP develops directly from the epiblast, triggered by nodal signal inhibition, and via the combined action of TFs SOX2, OTX2, POU3F1, and ZIC2, which promotes the the ANP development and inhibits other cell lineages...
June 2016: Development, Growth & Differentiation
Hidekiyo Harada, Tatsuya Sato, Harukazu Nakamura
In this paper, we review how midbrain and hindbrain are specified. Otx2 and Gbx2 are expressed from the early phase of development, and their expression abuts at the midbrain hindbrain boundary (MHB), where Fgf8 expression is induced, and functions as an organizing molecule for the midbrain and hindbrain. Fgf8 induces En1 and Pax2 expression at the region where Otx2 is expressed to specify midbrain. Fgf8 activates Ras-ERK pathway to specify hindbrain. Downstream of ERK, Pea3 specifies isthmus (rhombomere 0, r0), and Irx2 may specify r1, where the cerebellum is formed...
June 2016: Development, Growth & Differentiation
Virginie Dinet, Giuseppe D Ciccotosto, Kimberley Delaunay, Céline Borras, Isabelle Ranchon-Cole, Corinne Kostic, Michèle Savoldelli, Mohamed El Sanharawi, Laurent Jonet, Caroline Pirou, Na An, Marc Abitbol, Yvan Arsenijevic, Francine Behar-Cohen, Roberto Cappai, Frédéric Mascarelli
BACKGROUND: Amyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO). RESULTS: Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults...
2016: Molecular Brain
Ade Kallas-Kivi, Annika Trei, Toivo Maimets
The lipophilic statin lovastatin decreases cholesterol synthesis and is a safe and effective treatment for the prevention of cardiovascular diseases. Growing evidence points at antitumor potential of lovastatin. Therefore, understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design. In this study, we investigated the effects of lovastatin on the differentiation potential of human embryonic stem (hES) cells (H9 cell line). Multiparameter flow cytometric assay was used to detect changes in the expression of transcription factors characteristic of hES cells...
2016: Stem Cells International
Clémence Bernard, Clémentine Vincent, Damien Testa, Eva Bertini, Jérôme Ribot, Ariel A Di Nardo, Michel Volovitch, Alain Prochiantz
During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid...
May 2016: PLoS Genetics
Lena Iwai, Anna Ramos, Ari Schaler, Samuel Weinreb, Richard Blazeski, Carol Mason
In the developing murine eye, melanin synthesis in the retinal pigment epithelium (RPE) coincides with neurogenesis of retinal ganglion cells (RGCs). Disruption of pigmentation in the albino RPE is associated with delayed neurogenesis in the ventrotemporal retina, the source of ipsilateral RGCs, and a reduced ipsilateral RGC projection. To begin to unravel how melanogenesis and the RPE regulate RGC neurogenesis and cell subpopulation specification, we have compared the features of albino and pigmented mouse RPE cells during the period of RGC neurogenesis (embryonic day,E, 12...
April 21, 2016: Journal of Comparative Neurology
Angelica Navarra, Anna Musto, Anna Gargiulo, Giuseppe Petrosino, Giovanna Maria Pierantoni, Alfredo Fusco, Tommaso Russo, Silvia Parisi
BACKGROUND: A crucial event in the differentiation of mouse embryonic stem cells (ESCs) is the exit from the pluripotent ground state that leads to the acquisition of the 'primed' pluripotent phenotype, characteristic of the epiblast-like stem cells (EpiLCs). The transcription factors Oct4 and Otx2 play a key role in this phenomenon. In particular, Otx2 pioneers and activates new enhancers, which are silent in ESCs and which control the transcription of genes responsible for the acquisition of the EpiLC phenotype...
2016: BMC Biology
Jia-Wen Leong, Syahril Abdullah, King-Hwa Ling, Pike-See Cheah
MicroRNAs (miRNAs) are small noncoding RNA known to regulate brain development. The expression of two novel miRNAs, namely, miR-344b and miR-344c, was characterized during mouse brain developmental stages in this study. In situ hybridization analysis showed that miR-344b and miR-344c were expressed in the germinal layer during embryonic brain developmental stages. In contrast, miR-344b was not detectable in the adult brain while miR-344c was expressed exclusively in the adult olfactory bulb and cerebellar granular layer...
2016: Neural Plasticity
Peng Li, Xiaofeng Sun, Zhizhong Ma, Yinan Liu, Ying Jin, Ruimin Ge, Limin Hao, Yanling Ma, Shuo Han, Haojie Sun, Mingzhi Zhang, Ruizhi Li, Tao Li, Li Shen
Directed differentiation of human induced pluripotent stem cells (iPSCs) into retinal pigmented epithelium (RPE) holds great promise in cell replacement therapy for patients suffering from degenerative eye diseases, including age-related macular degeneration (AMD). In this study, we generated iPSCs from human dermal fibroblasts (HDFs) by electroporation with episomal plasmid vectors encoding OCT4, SOX2, KLF4, L-MYC together with p53 suppression. Intriguingly, cell reprogramming resulted in a metastable transcriptional activation and selective demethylation of neural and retinal specification-associated genes, such as OTX2, RX1 and SIX3...
2016: International Journal of Biological Sciences
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