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      Primary cilia biogenesis and associated retinal ciliopathies

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          Abstract

          The primary cilium is a ubiquitous microtubule-based organelle that senses external environment and modulates diverse signaling pathways in different cell types and tissues. The cilium originates from the mother centriole through a complex set of cellular events requiring hundreds of distinct components. Aberrant ciliogenesis or ciliary transport leads to a broad spectrum of clinical entities with overlapping yet highly variable phenotypes, collectively called ciliopathies, which include sensory defects and syndromic disorders with multi-organ pathologies. For efficient light detection, photoreceptors in the retina elaborate a modified cilium known as the outer segment, which is packed with membranous discs enriched for components of the phototransduction machinery. Retinopathy phenotype involves dysfunction and/or degeneration of the light sensing photoreceptors and is highly penetrant in ciliopathies. This review will discuss primary cilia biogenesis and ciliopathies, with a focus on the retina, and the role of CP110-CEP290-CC2D2A network. We will also explore how recent technologies can advance our understanding of cilia biology and discuss new paradigms for developing potential therapies of retinal ciliopathies.

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          Most cited references242

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          Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM).

          We have developed a high-resolution fluorescence microscopy method based on high-accuracy localization of photoswitchable fluorophores. In each imaging cycle, only a fraction of the fluorophores were turned on, allowing their positions to be determined with nanometer accuracy. The fluorophore positions obtained from a series of imaging cycles were used to reconstruct the overall image. We demonstrated an imaging resolution of 20 nm. This technique can, in principle, reach molecular-scale resolution.
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            Genes and molecular pathways underpinning ciliopathies

            Motile and non-motile primary cilia are nearly ubiquitous cellular organelles. Dysfunction of cilia is being found to cause increasing numbers of diseases that are known as ciliopathies. The characterization of ciliopathy-associated proteins and phenotypes is increasing our understanding of how cilia are formed and compartmentalized and how they function to maintain human health.
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              Self-formation of optic cups and storable stratified neural retina from human ESCs.

              In this report, we demonstrate that an optic cup structure can form by self-organization in human ESC culture. The human ESC-derived optic cup is much larger than the mouse ESC-derived one, presumably reflecting the species differences. The neural retina in human ESC culture is thick and spontaneously curves in an apically convex manner, which is not seen in mouse ESC culture. In addition, human ESC-derived neural retina grows into multilayered tissue containing both rods and cones, whereas cone differentiation is rare in mouse ESC culture. The accumulation of photoreceptors in human ESC culture can be greatly accelerated by Notch inhibition. In addition, we show that an optimized vitrification method enables en bloc cryopreservation of stratified neural retina of human origin. This storage method at an intermediate step during the time-consuming differentiation process provides a versatile solution for quality control in large-scale preparation of clinical-grade retinal tissues. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                9607332
                20707
                Semin Cell Dev Biol
                Semin Cell Dev Biol
                Seminars in cell & developmental biology
                1084-9521
                1096-3634
                28 August 2020
                31 July 2020
                February 2021
                09 February 2021
                : 110
                : 70-88
                Affiliations
                Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, MSC0610, 6 Center Drive, Bethesda, MD 20892, USA
                Author notes
                [* ]Corresponding authors: holly.chen@ 123456nih.gov (H.Y. Chen), swaroopa@ 123456nei.nih.gov (A. Swaroop).
                Article
                NIHMS1621297
                10.1016/j.semcdb.2020.07.013
                7855621
                32747192
                89955a84-2dab-4515-b506-222347216517

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/BY/4.0/)

                History
                Categories
                Article

                Developmental biology
                sensory cilia,ciliogenesis,photoreceptor,retinal degeneration,cep290,intracellular transport

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