TY - JOUR
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
N1 - Funding Information:
We would like to acknowledge Dr Xinhua Shu (Glasgow Caledonian University) for kindly housing the Rpgr KO mice. We would also like to thank CB, HB, MB and KR for their generous tissue donation to generate the iPSCs. This work was supported by grants from the Wellcome Trust (R.M., H.A. by Grant Number 100470/Z/12/Z; C.f.-C. by an Investigator Award), Retinitis Pigmentosa Fighting Blindness (R.M., H.A., A.F.W.; Grant Number GR583), the Academy of Medical Sciences (R.M., M.J.; Grant Number SGL014 \1011), a Medical Research Council Programme Grant (A.F.W.), an ERC Fellowship (C.M., M.L.), a DFG Grant (C.G., W.W.; Grant Number SPP1464) and the NIH (W.Z., H.K.; Grant Number EY022372).
PY - 2017/8/18
Y1 - 2017/8/18
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85027493467&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-00111-8
DO - 10.1038/s41467-017-00111-8
M3 - Article
C2 - 28814713
AN - SCOPUS:85027493467
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 271
ER -
