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Maciej Daniszewski, Anne Senabouth, Quan H Nguyen, Duncan E Crombie, Samuel W Lukowski, Tejal Kulkarni, Valentin M Sluch, Jafar S Jabbari, Xitiz Chamling, Donald J Zack, Alice Pébay, Joseph E Powell, Alex W Hewitt
We used single cell sequencing technology to characterize the transcriptomes of 1,174 human embryonic stem cell-derived retinal ganglion cells (RGCs) at the single cell level. The human embryonic stem cell line BRN3B-mCherry (A81-H7), was differentiated to RGCs using a guided differentiation approach. Cells were harvested at day 36 and prepared for single cell RNA sequencing. Our data indicates the presence of three distinct subpopulations of cells, with various degrees of maturity. One cluster of 288 cells showed increased expression of genes involved in axon guidance together with semaphorin interactions, cell-extracellular matrix interactions and ECM proteoglycans, suggestive of a more mature RGC phenotype...
February 13, 2018: Scientific Data
Wataru Kobayashi, Akishi Onishi, Hung-Ya Tu, Yuji Takihara, Michiru Matsumura, Kazuko Tsujimoto, Masaru Inatani, Toru Nakazawa, Masayo Takahashi
Purpose: We aimed to establish purification and culture systems for retinal ganglion cells (RGCs) differentiated from mouse and human pluripotent stem cells (PSC) for in vitro and regenerative medicine studies. Methods: We used a two-step immunopanning method to purify RGCs from mouse and human PSC-derived three-dimensional (3D) retinal organoids. To assess the method, we purified RGCs from 3D retinal organoids derived from embryonic stem cells (ESCs) generated from Thy1-EGFP transgenic (TG) mice...
February 1, 2018: Investigative Ophthalmology & Visual Science
Nadia Parmhans, Szilard Sajgo, Jingwen Niu, Wenqin Luo, Tudor Constantin Badea
We report the retinal expression pattern of Ret, a receptor tyrosine kinase for the glial derived neurotrophic factor (GDNF) family ligands (GFLs), during development and in the adult mouse. Ret is initially expressed in retinal ganglion cells (RGCs), followed by horizontal cells (HCs) and amacrine cells (ACs), beginning with the early stages of postmitotic development. Ret expression persists in all three classes of neurons in the adult. Using RNA sequencing, immunostaining and random sparse recombination, we show that Ret is expressed in at least three distinct types of ACs, and ten types of RGCs...
March 1, 2018: Journal of Comparative Neurology
Zuberwasim Sayyad, Kapil Sirohi, Vegesna Radha, Ghanshyam Swarup
A photoreceptor cell line, 661W, derived from a mouse retinal tumor that expresses several markers of cone photoreceptor cells has been described earlier. However, these cells can be differentiated into neuronal cells. Here, we report that this cell line expressed certain markers specific to retinal ganglion cells such as Rbpms, Brn3b (Pou4f2), Brn3c (Pou4f3), Thy1 and γ-synuclein (Sncg), and some other markers of neuronal cells (beta-III tubulin, NeuN and MAP2). These cells also expressed Opn1mw, a cone-specific marker and nestin, a marker for neural precursor cells...
December 4, 2017: Scientific Reports
Valentin M Sluch, Xitiz Chamling, Melissa M Liu, Cynthia A Berlinicke, Jie Cheng, Katherine L Mitchell, Derek S Welsbie, Donald J Zack
Human pluripotent stem cells have the potential to promote biological studies and accelerate drug discovery efforts by making possible direct experimentation on a variety of human cell types of interest. However, stem cell cultures are generally heterogeneous and efficient differentiation and purification protocols are often lacking. Here, we describe the generation of clustered regularly-interspaced short palindromic repeats(CRISPR)-Cas9 engineered reporter knock-in embryonic stem cell lines in which tdTomato and a unique cell-surface protein, THY1...
November 2017: Stem Cells Translational Medicine
Li Huang, Mengfei Chen, Weizhong Zhang, Xuerong Sun, Bingqian Liu, Jian Ge
Induced pluripotent stem cells (iPSCs) possess the capacity to differentiate into multiple cell types including retinal neurons. Despite substantial progress in the transcriptional regulation of iPSC differentiation process, the efficiency of generation of retinal neurons from iPSCs is still low. In this study, we investigated the role of transcription factor NeuroD1 in the differentiation of iPSCs into retinal neurons. We observed that retrovirus-mediated NeuroD1 overexpression in iPSCs increased the efficiency of neuronal differentiation...
January 2018: Molecular and Cellular Biochemistry
Lynda Erskine, Urielle François, Laura Denti, Andy Joyce, Miguel Tillo, Freyja Bruce, Neil Vargesson, Christiana Ruhrberg
Visual information is relayed from the eye to the brain via retinal ganglion cell (RGC) axons. Mice lacking NRP1 or NRP1-binding VEGF-A isoforms have defective RGC axon organisation alongside brain vascular defects. It is not known whether axonal defects are caused exclusively by defective VEGF-A signalling in RGCs or are exacerbated by abnormal vascular morphology. Targeted NRP1 ablation in RGCs with a Brn3bCre knock-in allele reduced axonal midline crossing at the optic chiasm and optic tract fasciculation...
July 1, 2017: Development
Szilard Sajgo, Miruna Georgiana Ghinia, Matthew Brooks, Friedrich Kretschmer, Katherine Chuang, Suja Hiriyanna, Zhijian Wu, Octavian Popescu, Tudor Constantin Badea
Visual information is conveyed from the eye to the brain by distinct types of retinal ganglion cells (RGCs). It is largely unknown how RGCs acquire their defining morphological and physiological features and connect to upstream and downstream synaptic partners. The three Brn3/Pou4f transcription factors (TFs) participate in a combinatorial code for RGC type specification, but their exact molecular roles are still unclear. We use deep sequencing to define (i) transcriptomes of Brn3a- and/or Brn3b-positive RGCs, (ii) Brn3a- and/or Brn3b-dependent RGC transcripts, and (iii) transcriptomes of retinorecipient areas of the brain at developmental stages relevant for axon guidance, dendrite formation, and synaptogenesis...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
Qi Zhang, Jamie Zagozewski, Shaohong Cheng, Rajiv Dixit, Shunzhen Zhang, Jimmy de Melo, Xiuqian Mu, William H Klein, Nadean L Brown, Jeffrey T Wigle, Carol Schuurmans, David D Eisenstat
Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1 , Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1 / Dlx2 / Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1 / Dlx2 / Brn3b -null retinas than was predicted by combining features of the Brn3b single- and Dlx1 / Dlx2 double-knockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer...
May 1, 2017: Development
Neeru Jindal, Avijit Banik, Sudesh Prabhakar, Kim Vaiphie, Akshay Anand
Retinal ganglion cell layer (RGCs) is one of the important layers of retina, depleted in Glaucoma. Loss of RGC neurons is a major cellular mechanism involved in its pathogenesis resulting in severe vision loss. Stem cell therapy has emerged as a potential strategy to arrest the apoptotic loss of RGCs and also replace the degenerative cells in damaged retina. Here, we have investigated the incorporation and survival of mouse bone marrow derived Lin-ve stem cells in N-methyl-d-aspartate (NMDA)-induced mouse model of retinal degeneration...
July 2017: Journal of Cellular Biochemistry
Nitasha R Phatak, Dorota L Stankowska, Raghu R Krishnamoorthy
PURPOSE: Brn3b is a class IV POU domain transcription factor that plays an important role in the development of retinal ganglion cells (RGCs), RGC survival, and particularly axon growth and pathfinding. Our previous study demonstrated that recombinant adenoassociated virus serotype 2 (rAAV-2)-mediated overexpression of Brn3b in RGCs promoted neuroprotection in a rodent model of glaucoma. However, the mechanisms underlying neuroprotection of RGCs in rats overexpressing Brn3b in animal models of glaucoma remain largely unknown...
2016: Molecular Vision
Miruna Georgiana Ghinia, Elena Novelli, Szilard Sajgo, Tudor Constantin Badea, Enrica Strettoi
Ganglion cells (GCs), the retinal output neurons, receive synaptic inputs from bipolar and amacrine cells in the inner plexiform layer (IPL) and send information to the brain nuclei via the optic nerve. Although GCs constitute less than 1% of the total retinal cells, they occur in numerous types and are the first neurons formed during retinal development. Using Brn3a and Brn3b mutant mice in which the alkaline phosphatase gene was knocked-in (Badea et al. [Neuron] 2009;61:852-864; Badea and Nathans [Vision Res] 2011;51:269-279), we studied the general effects after gene removal on the retinal neuropil together with the consequences of lack of development of large numbers of GCs onto the remaining retinal neurons of the same class...
July 8, 2016: Journal of Comparative Neurology
Varsha Jain, Ipsit Srivastava, Shriya Palchaudhuri, Manvi Goel, Sumit K Sinha-Mahapatra, Narender K Dhingra
Pupillary light reflex (PLR) is an important clinical tool to assess the integrity of visual pathways. The available evidence suggests that melanopsin-expressing retinal ganglion cells (mRGCs) mediate PLR-driven by the classical photoreceptors (rods and cones) at low irradiances and by melanopsin activation at high irradiances. However, genetic or pharmacological elimination of melanopsin does not completely abolish PLR at high irradiances, raising the possibility that classical photoreceptors may have a role even at high irradiances...
2016: PloS One
Fei Deng, Mengfei Chen, Ying Liu, Huiling Hu, Yunfan Xiong, Chaochao Xu, Yuchun Liu, Kangjun Li, Jing Zhuang, Jian Ge
PURPOSE: As an alternative and desirable approach for regenerative medicine, human induced pluripotent stem cell (hiPSC) technology raises the possibility of developing patient-tailored cell therapies to treat intractable degenerative diseases in the future. This study was undertaken to guide human Tenon's capsule fibroblasts-derived iPSCs (TiPSCs) to differentiate along the retinal ganglion cell (RGC) lineage, aiming at producing appropriate cellular material for RGC regeneration. METHODS: By mimicking RGC genesis, we deliberately administered the whole differentiation process and directed the stage-specific differentiation of human TiPSCs toward an RGC fate via manipulation of the retinal inducers (DKK1+Noggin+Lefty A) alongside master gene (Atoh7) sequentially...
2016: Molecular Vision
Chunsheng Qu, Dandan Bian, Xue Li, Jian Xiao, Chunping Wu, Yue Li, Tian Jiang, Xiangtian Zhou, Jia Qu, Jie-Guang Chen
Retinal ganglion cells (RGCs) are projection neurons in the neural retina that relay visual information from the environment to the central nervous system. The early expression of MATH5 endows the post-mitotic precursors with RGC competence and leads to the activation ofBrn3bthat marks committed RGCs. Nevertheless, this fate commitment process and, specifically, regulation ofBrn3bremain elusive. To explore the molecular mechanisms underlying RGC generation in the mouse retina, we analyzed the expression and function of Fez family zinc finger 2 (FEZF2), a transcription factor critical for the development of projection neurons in the cerebral cortex...
April 1, 2016: Journal of Biological Chemistry
K A Fernandes, S J Bloomsburg, C J Miller, S A Billingslea, M M Merrill, R W Burgess, R T Libby, P G Fuerst
The Down syndrome cell adhesion molecule gene (Dscam) is required for normal dendrite patterning and promotes developmental cell death in the mouse retina. Loss-of-function studies indicate that Dscam is required for refinement of retinal ganglion cell (RGC) axons in the lateral geniculate nucleus, and in this study we report and describe a requirement for Dscam in the maintenance of RGC axon projections within the retina. Mouse Dscam loss of function phenotypes related to retinal ganglion cell axon outgrowth and targeting have not been previously reported, despite the abundance of axon phenotypes reported in Drosophila Dscam1 loss and gain of function models...
March 2016: Molecular and Cellular Neurosciences
Szilard Sajgo, Seid Ali, Octavian Popescu, Tudor Constantin Badea
During development, transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors but rather emerge through the intersection of their expression domains. Brn3a, Brn3b, and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of retinal ganglion cells (RGC), spiral and vestibular ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the dorsal root ganglia...
April 1, 2016: Journal of Comparative Neurology
Ratnesh K Singh, Ramya K Mallela, Pamela K Cornuet, Aaron N Reifler, Andrew P Chervenak, Michael D West, Kwoon Y Wong, Igor O Nasonkin
Stem cell-based therapy of retinal degenerative conditions is a promising modality to treat blindness, but requires new strategies to improve the number of functionally integrating cells. Grafting semidifferentiated retinal tissue rather than progenitors allows preservation of tissue structure and connectivity in retinal grafts, mandatory for vision restoration. Using human embryonic stem cells (hESCs), we derived retinal tissue growing in adherent conditions consisting of conjoined neural retina and retinal pigment epithelial (RPE) cells and evaluated cell fate determination and maturation in this tissue...
December 1, 2015: Stem Cells and Development
Dana Morzaev, James D Nicholson, Tomm Caspi, Shirel Weiss, Edith Hochhauser, Nitza Goldenberg-Cohen
BACKGROUND: This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice. METHODS: ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b...
September 2015: Clinical & Experimental Ophthalmology
Taku Tanaka, Tadashi Yokoi, Fuminobu Tamalu, Shu-Ichi Watanabe, Sachiko Nishina, Noriyuki Azuma
We generated self-induced retinal ganglion cells (RGCs) with functional axons from human induced pluripotent stem cells. After development of the optic vesicle from the induced stem cell embryoid body in three-dimensional culture, conversion to two-dimensional culture, achieved by supplementation with BDNF, resulted in differentiation of RGCs at a rate of nearly 90% as indicated by a marginal subregion of an extruded clump of cells, suggesting the formation of an optic vesicle. Axons extended radially from the margin of the clump...
2015: Scientific Reports
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