July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Delivery and deployment of a ciliary actin dynamics module by PCARE drives the neogenesis of phototransductive membrane disks
Author Affiliations & Notes
  • Rob W J Collin
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Julio Cesar Corral Serrano
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Jeroen van Reeuwijk
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Anita DM Hoogendoorn
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Renate AA Ruigrok
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Adem Yildirim
    Johannes Gutenberg University of Mainz, Mainz, Germany
  • Stef JF Letteboer
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Lonneke Duijkers
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Sanae Sakami
    Case Western Reserve University, Cleveland, Ohio, United States
  • Krzysztof Palczewski
    Case Western Reserve University, Cleveland, Ohio, United States
  • Karsten Boldt
    University of Tuebingen, Tuebingen, Germany
  • Uwe Wolfrum
    Johannes Gutenberg University of Mainz, Mainz, Germany
  • Marius Ueffing
    University of Tuebingen, Tuebingen, Germany
  • Alex Garanto
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Ronald Roepman
    Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Rob Collin, None; Julio Cesar Corral Serrano, None; Jeroen van Reeuwijk, None; Anita Hoogendoorn, None; Renate Ruigrok, None; Adem Yildirim, None; Stef Letteboer, None; Lonneke Duijkers, None; Sanae Sakami, None; Krzysztof Palczewski, None; Karsten Boldt, None; Uwe Wolfrum, None; Marius Ueffing, None; Alex Garanto, None; Ronald Roepman, None
  • Footnotes
    Support  This work was funded by the FP7-PEOPLE-2012-ITN programme EyeTN, Brussels, Belgium (grant agreement no.: 317472) to RWJC
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4979. doi:https://doi.org/
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      Rob W J Collin, Julio Cesar Corral Serrano, Jeroen van Reeuwijk, Anita DM Hoogendoorn, Renate AA Ruigrok, Adem Yildirim, Stef JF Letteboer, Lonneke Duijkers, Sanae Sakami, Krzysztof Palczewski, Karsten Boldt, Uwe Wolfrum, Marius Ueffing, Alex Garanto, Ronald Roepman; Delivery and deployment of a ciliary actin dynamics module by PCARE drives the neogenesis of phototransductive membrane disks. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4979. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Various loss-of-function mutations in C2orf71 are known to cause inherited retinal dystrophies such as retinitis pigmentosa (RP). Yet, very little is still known about the protein encoded by this gene. In this study, we aimed to unravel the molecular function of C2orf71, and understand the pathophysiological mechanism underlying C2orf71-associated RP.

Methods : We have performed an affinity proteomics approach to identify binding partners of the protein product of the C2orf71 gene. Interactions were confirmed via co-immunoprecipitation and immunofluorescence studies, in ciliated cells as well as in a C2orf71-/- mutant mouse model. The intriguing occurrence of ciliary evaginations was further studied via co-transfections and high-resolution microscopy.

Results : We identified that an extensive actin assembly module was recruited to the tip of the connecting cilium stalk at the base of the outer segment by C2orf71, which we therefore coined PCARE (photoreceptor cilium actin regulator). Nucleated by the Arp2/3 activator WASF3, a dynamic branched F-actin network, resembling that of lamellipodia, drove the membrane evagination at the very onset of OS disk neogenesis, a process that was abrogated in C2orf71/Pcare-/- mice. Ectopic co-expression of PCARE and WASF3 in ciliated cells mimicked this evagination process at the ciliary tip. Furthermore, this process was disrupted by a retinal dystrophy-associated missense mutation in PCARE, emphasizing that disturbance of this actin dynamics-driven process can underlie RP.

Conclusions : The observation that several proteins involved in non-syndromic and syndromic retinal ciliopathies take part in the ciliary membrane evagination suggests that it is an important common denominator in the retinal pathomechanisms of these hereditary disorders.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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