Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice
Zhenglin Yang, … , David S. Williams, Kang Zhang
Zhenglin Yang, … , David S. Williams, Kang Zhang
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2908-2916. https://doi.org/10.1172/JCI35891.
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Research Article

Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice

Abstract

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Authors

Zhenglin Yang, Yali Chen, Concepcion Lillo, Jeremy Chien, Zhengya Yu, Michel Michaelides, Martin Klein, Kim A. Howes, Yang Li, Yuuki Kaminoh, Haoyu Chen, Chao Zhao, Yuhong Chen, Youssef Tawfik Al-Sheikh, Goutam Karan, Denis Corbeil, Pascal Escher, Shin Kamaya, Chunmei Li, Samantha Johnson, Jeanne M. Frederick, Yu Zhao, Changguan Wang, D. Joshua Cameron, Wieland B. Huttner, Daniel F. Schorderet, Frances L. Munier, Anthony T. Moore, David G. Birch, Wolfgang Baehr, David M. Hunt, David S. Williams, Kang Zhang

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Figure 3

Immunohistochemical localization of human PROM1 and endogenous mouse PROM1 in PROM1 transgenic retinas at 1 month of age.

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Immunohistochemical localization of human PROM1 and endogenous mouse PRO...
(A–L) Localization of transgenic human PROM1 (red) and native mouse PROM1 (green). (A–C) C57BL/6 mice showed endogenous mouse PROM1 signal alone at the base of the OSs. (D–F) In PWT20 mice, human PROM1 and endogenous mouse PROM1 were normally localized to the base of the OSs. (G–L) In PMT3 and PMT14 retinas, mutant PROM1 was mislocalized throughout the photoreceptors from the ONL to the OSs, whereas endogenous mouse PROM1 signal was more restricted to the ISs and OSs. Both endogenous mouse PROM1 and mutant PROM1 showed strong immunolabeling in the myoid region of the ISs. (M–R) PROM1 (red) and PCDH21 (green) protein immunolocalization in WT and mutant PROM1 transgenic retinas. (M–O) In 1-month-old PWT20 mice, PCDH21 and PROM1 colocalized at the base of photoreceptor OSs. (P–R) In PMT14 mice, PCDH21 was mislocalized, as was PROM1, to the ONL. (S–U) WT PROM1 immunolocalization in Pcdh21–/– mice. WT PROM1 immunolabeling (S) was evident throughout OSs. PROM1 colocalized with the OS marker CNGCA1 (T) and not the IS marker, Na/K-ATPase (U). Note that CNGCA1 and Na/K-ATPase signals were correctly located within OS and IS compartments, similar to the normal immunolabeling pattern in the R373C mutant PROM1 transgenic mice. INL, inner nuclear layer; OPL, outer plexiform layer; IPL, inner plexiform layer; GC, ganglion cells. Scale bars: 20 μm.