CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids.
CRB1
NOTCH1
RAB11A
VPS35
WDFY1
autophagy
cell polarity
endolysosomal system
organoids
retina
retromer
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
12 09 2023
12 09 2023
Historique:
received:
22
12
2021
revised:
03
07
2023
accepted:
04
07
2023
medline:
15
9
2023
pubmed:
5
8
2023
entrez:
4
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37541258
pii: S2213-6711(23)00263-1
doi: 10.1016/j.stemcr.2023.07.001
pmc: PMC10545476
pii:
doi:
Substances chimiques
Eye Proteins
0
CRB1 protein, human
0
Membrane Proteins
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1793-1810Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interests 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.
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