Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death.
Arap1
Phagocytosis
Pigmentosa
RPE
Retinitis
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 07 2022
01 07 2022
Historique:
received:
12
10
2021
accepted:
16
06
2022
pubmed:
28
6
2022
medline:
27
7
2022
entrez:
27
6
2022
Statut:
ppublish
Résumé
Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1-/- mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynamics. Curiously, Arap1 expression was detected in Müller glia and retinal pigment epithelium (RPE), but not the photoreceptors themselves. In this study, we generated conditional knockout mice for Müller glia/RPE, Müller glia and RPE via targeting Rlbp1, Glast and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Vmd2-Cre Arap1tm1c/tm1c and Rlbp1-Cre Arap1tm1c/tm1c mice, but not Glast-Cre Arap1tm1c/tm1c mice, recapitulated the phenotype originally observed in germline Arap1-/- mice. Mass spectrometry analysis of human ARAP1 co-immunoprecipitation identified candidate binding partners of ARAP1, revealing potential interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking and endocytosis. Quantification of outer segment phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1-/- mice compared to Arap1+/+ controls. We conclude that Arap1 expression in RPE is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 35758026
pii: 276063
doi: 10.1242/dmm.049343
pmc: PMC9346516
pii:
doi:
Substances chimiques
ARAP1 protein, human
0
Adaptor Proteins, Signal Transducing
0
Agtrap protein, mouse
0
Carrier Proteins
0
GTPase-Activating Proteins
0
Banques de données
figshare
['10.6084/m9.figshare.19225416']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NEI NIH HHS
ID : K08 EY027463
Pays : United States
Organisme : NEI NIH HHS
ID : K08 EY028199
Pays : United States
Organisme : NIH HHS
ID : UM1 OD023221
Pays : United States
Organisme : NIH HHS
ID : R03 OD032622
Pays : United States
Organisme : NIH HHS
ID : S10 OD026918
Pays : United States
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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