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      Cytomatrix proteins CAST and ELKS regulate retinal photoreceptor development and maintenance

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          Abstract

          The retinal ribbon synapse is important for the processing of visual information. Hagiwara et al. show that the active zone proteins CAST and ELKS perform both redundant and unique functions in photoreceptors to promote the maturation, maintenance, and activity of ribbon synapses.

          Abstract

          At the presynaptic active zone (AZ), the related cytomatrix proteins CAST and ELKS organize the presynaptic release machinery. While CAST is known to regulate AZ size and neurotransmitter release, the role of ELKS and the integral system of CAST/ELKS together is poorly understood. Here, we show that CAST and ELKS have both redundant and unique roles in coordinating synaptic development, function, and maintenance of retinal photoreceptor ribbon synapses. A CAST/ELKS double knockout (dKO) mouse showed high levels of ectopic synapses and reduced responses to visual stimulation. Ectopic formation was not observed in ELKS conditional KO but progressively increased with age in CAST KO mice with higher rates in the dKO. Presynaptic calcium influx was strongly reduced in rod photoreceptors of CAST KO and dKO mice. Three-dimensional scanning EM reconstructions showed structural abnormalities in rod triads of CAST KO and dKO. Remarkably, AAV-mediated acute ELKS deletion after synapse maturation induced neurodegeneration and loss of ribbon synapses. These results suggest that CAST and ELKS work in concert to promote retinal synapse formation, transmission, and maintenance.

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          Most cited references 57

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          The presynaptic active zone.

          Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, I discuss the molecular composition and function of the active zone. Active zones are composed of an evolutionarily conserved protein complex containing as core constituents RIM, Munc13, RIM-BP, α-liprin, and ELKS proteins. This complex docks and primes synaptic vesicles for exocytosis, recruits Ca(2+) channels to the site of exocytosis, and positions the active zone exactly opposite to postsynaptic specializations via transsynaptic cell-adhesion molecules. Moreover, this complex mediates short- and long-term plasticity in response to bursts of action potentials, thus critically contributing to the computational power of a synapse. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release.

            The molecular organization of presynaptic active zones during calcium influx-triggered neurotransmitter release is the focus of intense investigation. The Drosophila coiled-coil domain protein Bruchpilot (BRP) was observed in donut-shaped structures centered at active zones of neuromuscular synapses by using subdiffraction resolution STED (stimulated emission depletion) fluorescence microscopy. At brp mutant active zones, electron-dense projections (T-bars) were entirely lost, Ca2+ channels were reduced in density, evoked vesicle release was depressed, and short-term plasticity was altered. BRP-like proteins seem to establish proximity between Ca2+ channels and vesicles to allow efficient transmitter release and patterned synaptic plasticity.
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              Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development.

              Understanding the molecular mechanisms by which distinct cell fate is determined during organogenesis is a central issue in development and disease. Here, using conditional gene ablation in mice, we show that the transcription factor Otx2 is essential for retinal photoreceptor cell fate determination and development of the pineal gland. Otx2-deficiency converted differentiating photoreceptor cells to amacrine-like neurons and led to a total lack of pinealocytes in the pineal gland. We also found that Otx2 transactivates the cone-rod homeobox gene Crx, which is required for terminal differentiation and maintenance of photoreceptor cells. Furthermore, retroviral gene transfer of Otx2 steers retinal progenitor cells toward becoming photoreceptors. Thus, Otx2 is a key regulatory gene for the cell fate determination of retinal photoreceptor cells. Our results reveal the key molecular steps required for photoreceptor cell-fate determination and pinealocyte development.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                05 November 2018
                : 217
                : 11
                : 3993-4006
                Affiliations
                [1 ]Department of Biochemistry, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
                [2 ]Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan
                [3 ]Department of Anatomy, Kurume University School of Medicine, Fukuoka, Japan
                [4 ]Institute for Auditory Neuroscience and Inner Ear Lab, University Medical Center Göttingen, Göttingen, Germany
                [5 ]Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
                [6 ]Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan
                [7 ]Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
                Author notes
                Correspondence to Tobias Moser: tmoser@ 123456gwdg.de
                [*]

                Y. Kitihara and C.P. Grabner contributed equally to this paper.

                Article
                201704076
                10.1083/jcb.201704076
                6219712
                30190286
                © 2018 Hagiwara et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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                Funding
                Funded by: Japan Society for the Promotion of Science, DOI https://doi.org/10.13039/501100001691;
                Award ID: 25830008
                Award ID: 15H04272
                Award ID: 16H05135
                Funded by: Ministry of Education, Culture, Sports, Science and Technology, DOI https://doi.org/10.13039/501100001700;
                Award ID: 17H05741
                Funded by: Japan Science and Technology Agency, DOI https://doi.org/10.13039/501100002241;
                Award ID: JPMJCR1751
                Funded by: University of Yamanashi
                Funded by: German Research Foundation
                Funded by: Collaborative Research Center 889
                Funded by: Max Planck Society
                Funded by: Elisabeth and Helmut Uhl Foundation
                Funded by: National Institute for Physiological Sciences, DOI https://doi.org/10.13039/501100006323;
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                Cell biology

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