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Veronica Ferrucci, Pasqualino de Antonellis, Francesco Paolo Pennino, Fatemeh Asadzadeh, Antonella Virgilio, Donatella Montanaro, Aldo Galeone, Iolanda Boffa, Ida Pisano, Iolanda Scognamiglio, Luigi Navas, Donatella Diana, Emilia Pedone, Sara Gargiulo, Matteo Gramanzini, Arturo Brunetti, Laura Danielson, Marianeve Carotenuto, Lucia Liguori, Antonio Verrico, Lucia Quaglietta, Maria Elena Errico, Valentina Del Monaco, Valeria D'Argenio, Felice Tirone, Angela Mastronuzzi, Vittoria Donofrio, Felice Giangaspero, Daniel Picard, Marc Remke, Livia Garzia, Craig Daniels, Olivier Delattre, Fredrik J Swartling, William A Weiss, Francesco Salvatore, Roberto Fattorusso, Louis Chesler, Michael D Taylor, Giuseppe Cinalli, Massimo Zollo
Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition...
February 27, 2018: Brain: a Journal of Neurology
Xiaomin Su, Chenglei Wu, Xiaoying Ye, Ming Zeng, Zhujun Zhang, Yongzhe Che, Yuan Zhang, Lin Liu, Yushuang Lin, Rongcun Yang
TRIM family members have been implicated in a variety of biological processes such as differentiation and development. We here found that Trim59 plays a critical role in early embryo development from blastocyst stage to gastrula. There existed delayed development and empty yolk sacs from embryonic day (E) 8.5 in Trim59-/- embryos. No viable Trim59-/- embryos were observed beyond E9.5. Trim59 deficiency affected primary germ layer formation at the beginning of gastrulation. At E6.5 and E7.5, the expression of primary germ layer formation-associated genes including Brachyury, lefty2, Cer1, Otx2, Wnt3, and BMP4 was reduced in Trim59-/- embryos...
February 21, 2018: Cell Death & Disease
Nair Gopinathan Vidya, Sankaranarayanan Rajkumar, Abhay R Vasavada
BACKGROUND: Mutation in eye developmental genes has been reported to cause anophthalmia and microphthalmia. However, in India, especially in the Western Indian population, such reports are scarce. Hence, the present study aims to investigate mutations in 15 ocular developmental genes in patients with anophthalmia and microphthalmia in the western region of India. MATERIALS AND METHODS: Genomic DNA was isolated from the blood of 52 individuals affected with microphthalmia and anophthalmia, and 50 healthy normal controls...
February 20, 2018: Ophthalmic Genetics
Shinji Miyata, Satomi Nadanaka, Michihiro Igarashi, Hiroshi Kitagawa
Aggrecan, a chondroitin sulfate (CS) proteoglycan, forms lattice-like extracellular matrix structures called perineuronal nets (PNNs). Neocortical PNNs primarily ensheath parvalbumin-expressing inhibitory neurons (parvalbumin, PV cells) late in brain development. Emerging evidence indicates that PNNs promote the maturation of PV cells by enhancing the incorporation of homeobox protein Otx2 and regulating experience-dependent neural plasticity. Wisteria floribunda agglutinin (WFA), an N-acetylgalactosamine-specific plant lectin, binds to the CS chains of aggrecan and has been widely used to visualize PNNs...
2018: Frontiers in Integrative Neuroscience
Hisato Kondoh
Pioneered by the classical mouse embryonic stem cells (ESCs), various stem cell lines representing the peri- and postimplantation stages of embryogenesis have been established. To gain insight into the gene regulatory network operating in these cells, we first investigated epiblast stem cells (EpiSCs), performing ChIP-seq analysis for five major transcription factors (TFs) involved in epiblast regulation. The analysis indicated that SOX2-POU5F1 TF pairs highlighted in mouse ESCs are not the major players in other stem cells...
2018: Advances in Experimental Medicine and Biology
Gokul Kesavan, Juliane Hammer, Stefan Hans, Michael Brand
New genome-editing approaches, such as the CRISPR/Cas system, have opened up great opportunities to insert or delete genes at targeted loci and have revolutionized genetics in model organisms like the zebrafish. The Cre-loxp recombination system is widely used to activate or inactivate genes with high spatial and temporal specificity. Using a CRISPR/Cas9-mediated knock-in strategy, we inserted a zebrafish codon-optimized CreER T2 transgene at the otx2 gene locus to generate a conditional Cre-driver line. We chose otx2 as it is a patterning gene of the anterior neural plate that is expressed during early development...
February 12, 2018: Cell and Tissue Research
Zhenghui Su, Yanqi Zhang, Baojian Liao, Xiaofen Zhong, Xin Chen, Haitao Wang, Yiping Guo, Yongli Shan, Lihui Wang, Guangjin Pan
During neurogenesis, neural patterning is a critical step during which neural progenitor cells (NPCs) differentiate into neurons with distinct functions. However, the molecular determinants that regulate neural patterning remain poorly understood. Here, we optimized the "dual-SMAD inhibition" method to specifically promote differentiation of human pluripotent stem cells (hPSCs) into forebrain and hindbrain NPCs along the rostral-caudal (R-C) axes. We report that neural patterning determination occurs at the very early stage in this differentiation...
January 31, 2018: Journal of Biological Chemistry
Margaret Stromecki, Nazanin Tatari, Ludivine Coudière Morrison, Ravinder Kaur, Jamie Zagozewski, Gareth Palidwor, Vijay Ramaswamy, Patryk Skowron, Matthias Wölfl, Till Milde, Marc R Del Bigio, Michael D Taylor, Tamra Werbowetski-Ogilvie
Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo...
January 27, 2018: Molecular Oncology
Tomokazu Fukuda, Yasushi Ishizawa, Kenichiro Donai, Eriko Sugano, Hiroshi Tomita
The introduction of four key transcriptional factors (CRX, RAX, NEURO-D, OTX2) allows the direct differentiation of fibroblasts to retinal photoreceptor cells. This reprogramming was achieved with a combination of mono-cistronic viruses. Although the combination of mono-cistronic viruses was useful, a relatively high titer of recombinant viruses was necessary because co-infections are required. To overcome this issue, we established a poly-cistronic expression system for direct reprogramming and analyzed the biological characteristics of introduced cells after the exogenous introduction...
January 29, 2018: Cell Biology International
Xiaolu Tang, Luyan Jiao, Meige Zheng, Yan Yan, Qi Nie, Ting Wu, Xiaomei Wan, Guofeng Zhang, Yonglin Li, Song Wu, Bin Jiang, Huaibin Cai, Pingyi Xu, Jinhai Duan, Xian Lin
Tau protein participates in microtubule stabilization, axonal transport, and protein trafficking. Loss of normal tau function will exert a negative effect. However, current knowledge on the impact of tau deficiency on the motor behavior and related neurobiological changes are controversial. In this study, we examined motor functions and analyzed several proteins implicated in the maintenance of midbrain dopaminergic (DA) neurons (mDANs) function of adult and aged tau+/+, tau+/-, tau-/- mice. We found tau deficiency could not induce significant motor disorders...
January 11, 2018: Neuroscience
Maram Ea Abdalla-Elsayed, Patrik Schatz, Christine Neuhaus, Arif O Khan
Purpose: Heterozygous mutations in OTX2 have been associated with a range of ocular and pituitary abnormalities. We report a novel heterozygous deletion in OTX2 underlying early-onset retinal dystrophy with atypical maculopathy. Methods: Clinical examination included electroretinography and multimodal retinal imaging. Molecular genetic testing was composed of next-generation sequencing of a panel of retinal dystrophy genes. Results: A now 17-year-old boy presented 12 years earlier with a history of progressively poor vision since birth, nyctalopia, and early-onset retinal dystrophy with atypical maculopathy...
2017: Molecular Vision
Marina Riera, Ana Wert, Isabel Nieto, Esther Pomares
BACKGROUND: Microphthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single-gene analyses failed to identify the molecular cause. METHODS: A total of 47 genes previously associated with nonsyndromic MA were included in our panel...
November 2017: Molecular Genetics & Genomic Medicine
Divya S Varghese, Shama Parween, Mustafa T Ardah, Bright Starling Emerald, Suraiya A Ansari
Human embryonic stem cells (hESCs) are being used extensively in array of studies to understand different mechanisms such as early human embryogenesis, drug toxicity testing, disease modeling, and cell replacement therapy. The protocols for the directed differentiation of hESCs towards specific cell types often require long-term cell cultures. To avoid bacterial contamination, these protocols include addition of antibiotics such as pen-strep and gentamicin. Although aminoglycosides, streptomycin, and gentamicin have been shown to cause cytotoxicity in various animal models, the effect of these antibiotics on hESCs is not clear...
2017: Stem Cells International
Dario Acampora, Luca Giovanni Di Giovannantonio, Arcomaria Garofalo, Vincenzo Nigro, Daniela Omodei, Alessia Lombardi, Jingchao Zhang, Ian Chambers, Antonio Simeone
Embryonic stem cells (ESCs) cultured in leukemia inhibitory factor (LIF) plus fetal bovine serum (FBS) exhibit heterogeneity in the expression of naive and primed transcription factors. This heterogeneity reflects the dynamic condition of ESCs and their versatility to promptly respond to signaling effectors promoting naive or primed pluripotency. Here, we report that ESCs lacking Nanog or overexpressing Otx2 exhibit an early primed identity in LIF + FBS and fail to convert into 2i-induced naive state. Conversely, Otx2-null ESCs possess naive identity features in LIF + FBS similar to Nanog-overexpressing ESCs and convert poorly into FGF-induced early primed state...
November 14, 2017: Stem Cell Reports
Audrey Chabrat, Guillaume Brisson, Hélène Doucet-Beaupré, Charleen Salesse, Marcos Schaan Profes, Axelle Dovonou, Cléophace Akitegetse, Julien Charest, Suzanne Lemstra, Daniel Côté, R Jeroen Pasterkamp, Monica I Abrudan, Emmanouil Metzakopian, Siew-Lan Ang, Martin Lévesque
Mesodiencephalic dopamine neurons play central roles in the regulation of a wide range of brain functions, including voluntary movement and behavioral processes. These functions are served by distinct subtypes of mesodiencephalic dopamine neurons located in the substantia nigra pars compacta and the ventral tegmental area, which form the nigrostriatal, mesolimbic, and mesocortical pathways. Until now, mechanisms involved in dopaminergic circuit formation remained largely unknown. Here, we show that Lmx1a, Lmx1b, and Otx2 transcription factors control subtype-specific mesodiencephalic dopamine neurons and their appropriate axon innervation...
October 16, 2017: Nature Communications
Yue Li, Laijian Wang, Xinxin Zhang, Mengyao Huang, Sitong Li, Xinxing Wang, Lin Chen, Bin Jiang, Yupeng Yang
Cyclin-dependent kinase 5 (Cdk5) acts as an essential modulator for neural development and neurological disorders. Here we show that Cdk5 plays a pivotal role in modulating GABAergic signaling and the maturation of visual system. In adult mouse primary visual cortex, Cdk5 formed complex with the GABA synthetic enzyme glutamate decarboxylase GAD67, but not with GAD65. In addition to enhancement in the surface level of NR2B-containing NMDA receptors, inhibition of Cdk5 reduced the protein levels of GADs and Otx2, while leaving intact the expression of vesicular GABA transporter and subunits of GABAA or AMPA receptors...
January 2018: Neuropharmacology
Xue Zhang, Jocelyn M Biagini Myers, Veda K Yadagiri, Ashley Ulm, Xiaoting Chen, Matthew T Weirauch, Gurjit K Khurana Hershey, Hong Ji
BACKGROUND: Treatment response to systemic corticosteroid in asthmatic children is heterogeneous and may be mediated by epigenetic mechanism(s). We aim to identify DNA methylation (DNAm) changes responsive to steroid, and DNAm biomarkers that distinguish treatment response. MATERIALS AND METHODS: We followed 33 children (ages 5-18) presenting to the Emergency Department (ED) for asthma exacerbation. Based on whether they met discharge criteria in ≤24 hours, participants were grouped into good and poor responders to steroid treatment...
2017: PloS One
Christo Kole, Laurence Klipfel, Ying Yang, Vanessa Ferracane, Frederic Blond, Sacha Reichman, Géraldine Millet-Puel, Emmanuelle Clérin, Najate Aït-Ali, Delphine Pagan, Hawa Camara, Marie-Noëlle Delyfer, Emeline F Nandrot, Jose-Alain Sahel, Olivier Goureau, Thierry Léveillard
Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition...
September 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Xubin Hou, Nozomu Yoshioka, Hiroaki Tsukano, Akiko Sakai, Shinji Miyata, Yumi Watanabe, Yuchio Yanagawa, Kenji Sakimura, Kosei Takeuchi, Hiroshi Kitagawa, Takao K Hensch, Katsuei Shibuki, Michihiro Igarashi, Sayaka Sugiyama
Ocular dominance plasticity is easily observed during the critical period in early postnatal life. Chondroitin sulfate (CS) is the most abundant component in extracellular structures called perineuronal nets (PNNs), which surround parvalbumin-expressing interneurons (PV-cells). CS accumulates in PNNs at the critical period, but its function in earlier life is unclear. Here, we show that initiation of ocular dominance plasticity was impaired with reduced CS, using mice lacking a key CS-synthesizing enzyme, CSGalNAcT1...
October 3, 2017: Scientific Reports
Suganya Sivagurunathan, Jayamuruga Pandian Arunachalam, Subbulakshmi Chidambaram
Retinoblastoma (RB), a childhood cancer, is caused by biallelic mutation of the RB1 gene, but its development is not clearly understood. Furthermore, the presence of a cancer stem cell subpopulation in RB might impact its treatment. PIWI protein, known for its role in stem cell self-renewal, is aberrantly expressed in cancers. We examined the role of the PIWI-like protein HIWI2 in RB and its effect on the stem cell markers in cells of the RB line, Y79. The expression of HIWI2 is significantly increased in Y79 compared with its level in HeLa and ARPE19 cells...
2017: Cellular & Molecular Biology Letters
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