PRCD is essential for high-fidelity photoreceptor disc formation

William J. Spencer, Jin Dong Ding, Tylor R. Lewis, Chen Yu, Sebastien Phan, Jillian N. Pearring, Keun Young Kim, Andrea Thor, Rose Mathew, Joan Kalnitsky, Ying Hao, Amanda M. Travis, Sondip K. Biswas, Woo Kuen Lo, Joseph C. Besharse, Mark H. Ellisman, Daniel R. Saban, Marie E Burns, Vadim Y. Arshavsky

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

Original languageEnglish (US)
Pages (from-to)13087-13096
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number26
DOIs
StatePublished - Jan 1 2019

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Morphogenesis
Knockout Mice
Light
Membranes
Retinal Pigment Epithelium
Blindness
Phagocytosis
Proteins
Cone-Rod Dystrophies
Dogs
Mutation
Survival

Keywords

  • Microglia
  • Photoreceptor
  • PRCD
  • Retinal degeneration

ASJC Scopus subject areas

  • General

Cite this

Spencer, W. J., Ding, J. D., Lewis, T. R., Yu, C., Phan, S., Pearring, J. N., ... Arshavsky, V. Y. (2019). PRCD is essential for high-fidelity photoreceptor disc formation. Proceedings of the National Academy of Sciences of the United States of America, 116(26), 13087-13096. https://doi.org/10.1073/pnas.1906421116

PRCD is essential for high-fidelity photoreceptor disc formation. / Spencer, William J.; Ding, Jin Dong; Lewis, Tylor R.; Yu, Chen; Phan, Sebastien; Pearring, Jillian N.; Kim, Keun Young; Thor, Andrea; Mathew, Rose; Kalnitsky, Joan; Hao, Ying; Travis, Amanda M.; Biswas, Sondip K.; Lo, Woo Kuen; Besharse, Joseph C.; Ellisman, Mark H.; Saban, Daniel R.; Burns, Marie E; Arshavsky, Vadim Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 26, 01.01.2019, p. 13087-13096.

Research output: Contribution to journalArticle

Spencer, WJ, Ding, JD, Lewis, TR, Yu, C, Phan, S, Pearring, JN, Kim, KY, Thor, A, Mathew, R, Kalnitsky, J, Hao, Y, Travis, AM, Biswas, SK, Lo, WK, Besharse, JC, Ellisman, MH, Saban, DR, Burns, ME & Arshavsky, VY 2019, 'PRCD is essential for high-fidelity photoreceptor disc formation', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 26, pp. 13087-13096. https://doi.org/10.1073/pnas.1906421116
Spencer, William J. ; Ding, Jin Dong ; Lewis, Tylor R. ; Yu, Chen ; Phan, Sebastien ; Pearring, Jillian N. ; Kim, Keun Young ; Thor, Andrea ; Mathew, Rose ; Kalnitsky, Joan ; Hao, Ying ; Travis, Amanda M. ; Biswas, Sondip K. ; Lo, Woo Kuen ; Besharse, Joseph C. ; Ellisman, Mark H. ; Saban, Daniel R. ; Burns, Marie E ; Arshavsky, Vadim Y. / PRCD is essential for high-fidelity photoreceptor disc formation. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 26. pp. 13087-13096.
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AU - Pearring, Jillian N.

AU - Kim, Keun Young

AU - Thor, Andrea

AU - Mathew, Rose

AU - Kalnitsky, Joan

AU - Hao, Ying

AU - Travis, Amanda M.

AU - Biswas, Sondip K.

AU - Lo, Woo Kuen

AU - Besharse, Joseph C.

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N2 - Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

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