CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids

Thilo M Buck; Peter M J Quinn; Lucie P Pellissier; Aat A Mulder; Aldo Jongejan; Xuefei Lu; Nanda Boon; Daniëlle Koot; Hind Almushattat; Christiaan H Arendzen; Rogier M Vos; Edward J Bradley; Christian Freund; Harald M M Mikkers; Camiel J F Boon; Perry D Moerland; Frank Baas; Abraham J Koster; Jacques Neefjes; Ilana Berlin; Carolina R Jost; Jan Wijnholds

doi:10.1016/j.stemcr.2023.07.001

CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids

Thilo M Buck, Peter M J Quinn, Lucie P Pellissier, Aat A Mulder, Aldo Jongejan, Xuefei Lu, Nanda Boon, Daniëlle Koot, Hind Almushattat, Christiaan H Arendzen, Rogier M Vos, Edward J Bradley, Christian Freund, Harald M M Mikkers, Camiel J F Boon, Perry D Moerland, Frank Baas, Abraham J Koster, Jacques Neefjes, Ilana BerlinCarolina R Jost, Jan Wijnholds

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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.

Original language	English
Pages (from-to)	1793-1810
Journal	Stem Cell Reports
Volume	18
DOIs	https://doi.org/10.1016/j.stemcr.2023.07.001
Publication status	Published - 28 Jul 2023

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Buck2023Final published version, 7.42 MBLicence: CC BY

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Buck, T. M., Quinn, P. M. J., Pellissier, L. P., Mulder, A. A., Jongejan, A., Lu, X., Boon, N., Koot, D., Almushattat, H., Arendzen, C. H., Vos, R. M., Bradley, E. J., Freund, C., Mikkers, H. M. M., Boon, C. J. F., Moerland, P. D., Baas, F., Koster, A. J., Neefjes, J., ... Wijnholds, J. (2023). CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids. Stem Cell Reports, 18, 1793-1810. https://doi.org/10.1016/j.stemcr.2023.07.001

@article{c75cf77740fa4cbbba37ac64cc3f07b5,

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.",

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",

year = "2023",

month = jul,

day = "28",

doi = "10.1016/j.stemcr.2023.07.001",

language = "English",

volume = "18",

pages = "1793--1810",

journal = "Stem Cell Reports",

issn = "2213-6711",

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Buck, TM, Quinn, PMJ, Pellissier, LP, Mulder, AA, Jongejan, A, Lu, X, Boon, N, Koot, D, Almushattat, H, Arendzen, CH, Vos, RM, Bradley, EJ, Freund, C, Mikkers, HMM, Boon, CJF, Moerland, PD, Baas, F, Koster, AJ, Neefjes, J, Berlin, I, Jost, CR & Wijnholds, J 2023, 'CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids', Stem Cell Reports, vol. 18, pp. 1793-1810. https://doi.org/10.1016/j.stemcr.2023.07.001

TY - JOUR

T1 - CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids

AU - Buck, Thilo M

AU - Quinn, Peter M J

AU - Pellissier, Lucie P

AU - Mulder, Aat A

AU - Jongejan, Aldo

AU - Lu, Xuefei

AU - Boon, Nanda

AU - Koot, Daniëlle

AU - Almushattat, Hind

AU - Arendzen, Christiaan H

AU - Vos, Rogier M

AU - Bradley, Edward J

AU - Freund, Christian

AU - Mikkers, Harald M M

AU - Boon, Camiel J F

AU - Moerland, Perry D

AU - Baas, Frank

AU - Koster, Abraham J

AU - Neefjes, Jacques

AU - Berlin, Ilana

AU - Jost, Carolina R

AU - Wijnholds, Jan

PY - 2023/7/28

Y1 - 2023/7/28

N2 - 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.

AB - 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.

U2 - 10.1016/j.stemcr.2023.07.001

DO - 10.1016/j.stemcr.2023.07.001

M3 - Article

C2 - 37541258

SN - 2213-6711

VL - 18

SP - 1793

EP - 1810

JO - Stem Cell Reports

JF - Stem Cell Reports

ER -

CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids

Abstract

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