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5. Monitoring paxillin in astrocytes reveals the significance of the adhesion G protein coupled receptor VLGR1/ADGRV1 for focal adhesion assembly.

Author

Güler, Baran E., Linnert, Joshua, and Wolfrum, Uwe

Subjects
*FOCAL adhesions, *G protein coupled receptors, *ASTROCYTES, *USHER'S syndrome, *CELL migration, *CELL imaging
Abstract

VLGR1/ADGRV1 (very large G protein‐coupled receptor‐1) is the largest adhesion G protein‐coupled receptor (aGPCR). Mutations in VLGR1/ADGRV1 are associated with human Usher syndrome, the most common form of deaf‐blindness, and also with epilepsy in humans and mice. VLGR1 is expressed almost ubiquitously but is mainly found in the CNS and in the sensory cells of the eye and inner ear. Little is known about the pathogenesis of the diseases related to VLGR1. We previously identified VLGR1 as a vital component of focal adhesions (FAs) serving as a metabotropic mechanoreceptor controls cell spreading and migration. FAs are highly dynamic and turnover in response to internal and external signals. Here, we aimed to elucidate how VLGR1 participates in FA turnover. Nocodazole washouts and live cell imaging of paxillin‐DsRed2 consistently showed that FA disassembly was not altered, but de novo assembly of FA was significantly delayed in Vlgr1‐deficient astrocytes, indicating that VLGR1 is enrolled in FA assembly. In FRAP experiments, recovery rates were significantly reduced in Vlgr1‐deficient FAs, indicating reduced turnover kinetics in VLGR1‐deficient FAs. We showed that VLGR1 regulates cell migration by controlling the FA turnover during their assembly and expect novel insights into pathomechanisms related to pathogenic dysfunctions of VLGR1. [ABSTRACT FROM AUTHOR]

Published
2023
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9. The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Author

Turn, Rachel E., primary, Hu, Yihan, additional, Dewees, Skylar I., additional, Devi, Narra, additional, East, Michael P., additional, Hardin, Katherine R., additional, Khatib, Tala, additional, Linnert, Joshua, additional, Wolfrum, Uwe, additional, Lim, Michael J., additional, Casanova, James E., additional, Caspary, Tamara, additional, and Kahn, Richard A., additional

Published
2022
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10. Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

Author

Grotz, Sophia, Schäfer, Jessica, Wunderlich, Kirsten A, Ellederova, Zdenka, Auch, Hannah, Bähr, Andrea, Runa‐Vochozkova, Petra; https://orcid.org/0000-0003-3691-0340, Fadl, Janet, Arnold, Vanessa, Ardan, Taras, Veith, Miroslav; https://orcid.org/0000-0001-6254-436X, Santamaria, Gianluca, Dhom, Georg, Hitzl, Wolfgang; https://orcid.org/0000-0002-7696-1479, Kessler, Barbara; https://orcid.org/0000-0001-7036-238X, Eckardt, Christian, Klein, Joshua, Brymova, Anna, Linnert, Joshua, Kurome, Mayuko, Zakharchenko, Valeri, Fischer, Andrea, Blutke, Andreas, Döring, Anna, Suchankova, Stepanka, Popelar, Jiri, Rodríguez‐Bocanegra, Eduardo, Dlugaiczyk, Julia; https://orcid.org/0000-0001-7693-9127, Straka, Hans, May‐Simera, Helen; https://orcid.org/0000-0002-9477-4036, et al, Grotz, Sophia, Schäfer, Jessica, Wunderlich, Kirsten A, Ellederova, Zdenka, Auch, Hannah, Bähr, Andrea, Runa‐Vochozkova, Petra; https://orcid.org/0000-0003-3691-0340, Fadl, Janet, Arnold, Vanessa, Ardan, Taras, Veith, Miroslav; https://orcid.org/0000-0001-6254-436X, Santamaria, Gianluca, Dhom, Georg, Hitzl, Wolfgang; https://orcid.org/0000-0002-7696-1479, Kessler, Barbara; https://orcid.org/0000-0001-7036-238X, Eckardt, Christian, Klein, Joshua, Brymova, Anna, Linnert, Joshua, Kurome, Mayuko, Zakharchenko, Valeri, Fischer, Andrea, Blutke, Andreas, Döring, Anna, Suchankova, Stepanka, Popelar, Jiri, Rodríguez‐Bocanegra, Eduardo, Dlugaiczyk, Julia; https://orcid.org/0000-0001-7693-9127, Straka, Hans, May‐Simera, Helen; https://orcid.org/0000-0002-9477-4036, and et al

Abstract

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas-mediated gene repair or gene therapy in vitro. AAV-based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.

Published
2022

12. Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

Author

Grotz, Sophia, primary, Schäfer, Jessica, additional, Wunderlich, Kirsten A, additional, Ellederova, Zdenka, additional, Auch, Hannah, additional, Bähr, Andrea, additional, Runa‐Vochozkova, Petra, additional, Fadl, Janet, additional, Arnold, Vanessa, additional, Ardan, Taras, additional, Veith, Miroslav, additional, Santamaria, Gianluca, additional, Dhom, Georg, additional, Hitzl, Wolfgang, additional, Kessler, Barbara, additional, Eckardt, Christian, additional, Klein, Joshua, additional, Brymova, Anna, additional, Linnert, Joshua, additional, Kurome, Mayuko, additional, Zakharchenko, Valeri, additional, Fischer, Andrea, additional, Blutke, Andreas, additional, Döring, Anna, additional, Suchankova, Stepanka, additional, Popelar, Jiri, additional, Rodríguez‐Bocanegra, Eduardo, additional, Dlugaiczyk, Julia, additional, Straka, Hans, additional, May‐Simera, Helen, additional, Wang, Weiwei, additional, Laugwitz, Karl‐Ludwig, additional, Vandenberghe, Luk H, additional, Wolf, Eckhard, additional, Nagel‐Wolfrum, Kerstin, additional, Peters, Tobias, additional, Motlik, Jan, additional, Fischer, M Dominik, additional, Wolfrum, Uwe, additional, and Klymiuk, Nikolai, additional

Published
2022
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14. The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and Cilia to Regulate Ciliogenesis and Ciliary Protein Traffic

Author

Turn, Rachel E, primary, Hu, Yihan, additional, Dewees, Skylar I, additional, Devi, Narra, additional, East, Michael P, additional, Hardin, Katherine R, additional, Khatib, Tala, additional, Linnert, Joshua, additional, Wolfrum, Uwe, additional, Lim, Jun Y., additional, Casanova, James E., additional, Caspary, Tamara, additional, and Kahn, Richard A, additional

Published
2021
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15. The Adhesion GPCR VLGR1/ADGRV1 Regulates the Ca 2+ Homeostasis at Mitochondria-Associated ER Membranes.

Author

Krzysko, Jacek, Maciag, Filip, Mertens, Anna, Güler, Baran Enes, Linnert, Joshua, Boldt, Karsten, Ueffing, Marius, Nagel-Wolfrum, Kerstin, Heine, Martin, and Wolfrum, Uwe

Subjects
HOMEOSTASIS, FOCAL adhesions, G protein coupled receptors, CHILDHOOD epilepsy, USHER'S syndrome, MOLECULAR interactions, ORGANELLES, CELL compartmentation
Abstract

The very large G protein-coupled receptor (VLGR1, ADGRV1) is the largest member of the adhesion GPCR family. Mutations in VLGR1 have been associated with the human Usher syndrome (USH), the most common form of inherited deaf-blindness as well as childhood absence epilepsy. VLGR1 was previously found as membrane–membrane adhesion complexes and focal adhesions. Affinity proteomics revealed that in the interactome of VLGR1, molecules are enriched that are associated with both the ER and mitochondria, as well as mitochondria-associated ER membranes (MAMs), a compartment at the contact sites of both organelles. We confirmed the interaction of VLGR1 with key proteins of MAMs by pull-down assays in vitro complemented by in situ proximity ligation assays in cells. Immunocytochemistry by light and electron microscopy demonstrated the localization of VLGR1 in MAMs. The absence of VLGR1 in tissues and cells derived from VLGR1-deficient mouse models resulted in alterations in the MAM architecture and in the dysregulation of the Ca2+ transient from ER to mitochondria. Our data demonstrate the molecular and functional interaction of VLGR1 with components in MAMs and point to an essential role of VLGR1 in the regulation of Ca2+ homeostasis, one of the key functions of MAMs. [ABSTRACT FROM AUTHOR]

Published
2022
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16. Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome

Author

Grotz, Sophia, primary, Schäfer, Jessica, additional, Wunderlich, Kirsten A., additional, Ellederova, Zdenka, additional, Auch, Hannah, additional, Bähr, Andrea, additional, Runa-Vochozkova, Petra, additional, Plutniok, Janet, additional, Arnold, Vanessa, additional, Ardan, Taras, additional, Veith, Miroslav, additional, Santamaria, Gianluca, additional, Dhom, Georg, additional, Hitzl, Wolfgang, additional, Kessler, Barbara, additional, Kurome, Mayuko, additional, Zakharchenko, Valeri, additional, Linnert, Joshua, additional, Fischer, Andrea, additional, Blutke, Andreas, additional, Döring, Anna, additional, Suchankova, Stepanka, additional, Popelar, Jiri, additional, May-Simera, Helen, additional, Laugwitz, Karl-Ludwig, additional, Vandenberghe, Luk H., additional, Wolf, Eckhard, additional, Nagel-Wolfrum, Kerstin, additional, Motlik, Jan, additional, Fischer, M. Dominik, additional, Wolfrum, Uwe, additional, and Klymiuk, Nikolai, additional

Published
2021
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