Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Roly Megaw, Hashem Abu-Arafeh, Melissa Jungnickel, Carla Mellough, Christine Gurniak, Walter Witke, Wei Zhang, Hemant Khanna, Pleasantine Mill, Baljean Dhillon, Alan F Wright, Majlinda Lako, Charles Ffrench-Constant

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.

Original languageEnglish
Article number271
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 16 Aug 2017
Externally publishedYes

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Gelsolin
photoreceptors
Retinitis Pigmentosa
GTP Phosphohydrolases
regulators
animals
Animals
Actins
causes
cells
Photoreceptor Connecting Cilium
Rhodopsin
Retinal Dystrophies
mutations
knockout mice
Induced Pluripotent Stem Cells
stem cells
abnormalities
Polymerization
Mutation

Cite this

Megaw, Roly ; Abu-Arafeh, Hashem ; Jungnickel, Melissa ; Mellough, Carla ; Gurniak, Christine ; Witke, Walter ; Zhang, Wei ; Khanna, Hemant ; Mill, Pleasantine ; Dhillon, Baljean ; Wright, Alan F ; Lako, Majlinda ; Ffrench-Constant, Charles. / Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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abstract = "Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.",
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Megaw, R, Abu-Arafeh, H, Jungnickel, M, Mellough, C, Gurniak, C, Witke, W, Zhang, W, Khanna, H, Mill, P, Dhillon, B, Wright, AF, Lako, M & Ffrench-Constant, C 2017, 'Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models' Nature Communications, vol. 8, no. 1, 271. https://doi.org/10.1038/s41467-017-00111-8

Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models. / Megaw, Roly; Abu-Arafeh, Hashem; Jungnickel, Melissa; Mellough, Carla; Gurniak, Christine; Witke, Walter; Zhang, Wei; Khanna, Hemant; Mill, Pleasantine; Dhillon, Baljean; Wright, Alan F; Lako, Majlinda; Ffrench-Constant, Charles.

In: Nature Communications, Vol. 8, No. 1, 271, 16.08.2017.

Research output: Contribution to journalArticle

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T1 - Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

AU - Megaw, Roly

AU - Abu-Arafeh, Hashem

AU - Jungnickel, Melissa

AU - Mellough, Carla

AU - Gurniak, Christine

AU - Witke, Walter

AU - Zhang, Wei

AU - Khanna, Hemant

AU - Mill, Pleasantine

AU - Dhillon, Baljean

AU - Wright, Alan F

AU - Lako, Majlinda

AU - Ffrench-Constant, Charles

PY - 2017/8/16

Y1 - 2017/8/16

N2 - Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.

AB - Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.

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KW - Animals

KW - Carrier Proteins

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KW - Disease Models, Animal

KW - Eye Proteins

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KW - Induced Pluripotent Stem Cells

KW - Mice

KW - Mice, Knockout

KW - Photoreceptor Cells, Vertebrate

KW - Protein Transport

KW - Retinitis Pigmentosa

KW - Rhodopsin

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

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M3 - Article

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JF - Nature Communications

SN - 2041-1723

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