June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
The WAVE complex is an essential component of the actin network that initiates photoreceptor disc membrane morphogenesis
Author Affiliations & Notes
  • WILLIAM J SPENCER
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Nicholas F Schneider
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Nikolai P Skiba
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Vadim Y Arshavsky
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   WILLIAM SPENCER None; Nicholas Schneider None; Nikolai Skiba None; Vadim Arshavsky None
  • Footnotes
    Support  Knights Templar Career Starter Award
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1373 – F0304. doi:
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      WILLIAM J SPENCER, Nicholas F Schneider, Nikolai P Skiba, Vadim Y Arshavsky; The WAVE complex is an essential component of the actin network that initiates photoreceptor disc membrane morphogenesis. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1373 – F0304.

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

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Abstract

Purpose : The vertebrate photoreceptor cell’s outer segment is a highly modified primary cilium filled with hundreds of disc-shaped membranes known as “discs” which serve to efficiently capture light. To cope with light stress of disc membranes, photoreceptor cells constantly renew them. This is accomplished by the daily formation of new discs at the outer segment base and the engulfment of old discs from outer segment tips by the retinal pigment epithelium (RPE). The formation of each new disc begins at the base of the outer segment where Arp2/3 driven actin polymerization pushes out the ciliary membrane to form a membrane evagination. To drive actin polymerization, the Arp2/3 complex is known to require the activity of a nucleation promoting factor. Here, we sought to identify the nucleation promoting factor working with Arp2/3 during disc formation. Defects in disc morphogenesis underlie many blinding retinal diseases and understanding the basic molecular mechanism of the process lays the foundation for the development of future therapies.

Methods : We conducted a series of proteomic experiments to identify proteins potentially interacting with Arp2/3 at the site of disc formation. We identified protein isoforms representing all five members of the WAVE regulatory complex, including the nucleation promoting factor, Wasf3. We next analyzed the retinas of Wasf3–/– mice by Western blotting, light microscopy and electron microscopy.

Results : We found that the WAVE complex serves as the nucleation promoting factor for Arp2/3 at the site of disc formation. We identified the major protein isoforms of the WAVE complex present in rod outer segments, and showed that the absence of one of them, Wasf3, results in the complete loss of actin at the site of disc morphogenesis. Without the action of actin to initiate disc formation, the membranes delivered to the outer segment in Wasf3–/– mice grossly overgrow and their photoreceptors degenerate having disorganized membrane whorls emanating from their cilia rather than normal outer segments.

Conclusions : These data establish the WAVE complex as an essential component for photoreceptor disc morphogenesis and vertebrate vision.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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