@article{0f976b21a4404bb3b8e18eb5c127a2a9,
title = "CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids",
abstract = "CRB1 gene mutations can cause early- or late-onset retinitis pigmentosa, Leber congenital amaurosis, or maculopathy. Recapitulating human CRB1 phenotypes in animal models has proven challenging, necessitating the development of alternatives. We generated human induced pluripotent stem cell (iPSC)-derived retinal organoids of patients with retinitis pigmentosa caused by biallelic CRB1 mutations and evaluated them against autologous gene-corrected hiPSCs and hiPSCs from healthy individuals. Patient organoids show decreased levels of CRB1 and NOTCH1 expression at the retinal outer limiting membrane. Proximity ligation assays show that human CRB1 and NOTCH1 can interact via their extracellular domains. CRB1 patient organoids feature increased levels of WDFY1+ vesicles, fewer RAB11A+ recycling endosomes, decreased VPS35 retromer complex components, and more degradative endolysosomal compartments relative to isogenic control organoids. Taken together, our data demonstrate that patient-derived retinal organoids enable modeling of retinal degeneration and highlight the importance of CRB1 in early endosome maturation receptor recycling in the retina.",
keywords = "CRB1, NOTCH1, RAB11A, VPS35, WDFY1, autophagy, cell polarity, endolysosomal system, organoids, retina, retromer",
author = "Buck, {Thilo M.} and Quinn, {Peter M. J.} and Pellissier, {Lucie P.} and Mulder, {Aat A.} and Aldo Jongejan and Xuefei Lu and Nanda Boon and Dani{\"e}lle Koot and Hind Almushattat and Arendzen, {Christiaan H.} and Vos, {Rogier M.} and Bradley, {Edward J.} and Christian Freund and Mikkers, {Harald M. M.} and Boon, {Camiel J. F.} and Moerland, {Perry D.} and Frank Baas and Koster, {Abraham J.} and Jacques Neefjes and Ilana Berlin and Jost, {Carolina R.} and Jan Wijnholds",
note = "Funding Information: We thank Marco Heuvelman and Yacintha van Doorn for experimental work and the Wijnholds lab for advice on experiments and reviewing the manuscript. We thank Annelies Boonzaier-van der Laan and Lennard M. Voortman for technical assistance with microscopy and image analysis. Funding was provided by The Netherlands Organization for Health Research and Development (ZonMw grant 43200004 to J.W.), research grant MDBR-20-112-CRB1 from the University of Pennsylvania Orphan Disease Center in partnership with the Curing Retinal Blindness Foundation (to J.W.), research grant CRBF 2016-Aug-02 (to J.W.), LUMC Research Foundation Bontius Stichting 32072-8231, and the Dutch Blindness Funds (Uitzicht 2015-22 to J.W., Uitzicht 2020-01 to T.M.B. and J.W.): Rotterdamse Stichting Blindenbelangen, OogFonds, Stichting Blindenhulp, Stichting Retina Fonds, and Landelijke Stichting voor Blinden en Slechtzienden. Funding Information: We thank Marco Heuvelman and Yacintha van Doorn for experimental work and the Wijnholds lab for advice on experiments and reviewing the manuscript. We thank Annelies Boonzaier-van der Laan and Lennard M. Voortman for technical assistance with microscopy and image analysis. Funding was provided by The Netherlands Organization for Health Research and Development (ZonMw grant 43200004 to J.W.), research grant MDBR-20-112-CRB1 from the University of Pennsylvania Orphan Disease Center in partnership with the Curing Retinal Blindness Foundation (to J.W.), research grant CRBF 2016-Aug-02 (to J.W.), LUMC Research Foundation Bontius Stichting 32072-8231, and the Dutch Blindness Funds (Uitzicht 2015-22 to J.W. Uitzicht 2020-01 to T.M.B. and J.W.): Rotterdamse Stichting Blindenbelangen, OogFonds, Stichting Blindenhulp, Stichting Retina Fonds, and Landelijke Stichting voor Blinden en Slechtzienden. The authors declare no competing interests. The LUMC is holder of patent number PCT/NL2014/050549, which describes the potential clinical use of CRB2; J.W. and L.P.P. are listed as co-inventor of this patent, and J.W. is an employee of the LUMC. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = sep,
day = "12",
doi = "https://doi.org/10.1016/j.stemcr.2023.07.001",
language = "English",
volume = "18",
pages = "1793--1810",
journal = "Stem cell reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "9",
}