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ResearchIn-Press PreviewCell biologyNeuroscienceOphthalmology Open Access | 10.1172/JCI196705

Adam9-deficient retinal pigment epithelium pseudopods maintain photoreceptor outer segment renewal despite subretinal space expansion

Tylor R. Lewis,1 Carson M. Castillo,2 Sebastien Phan,3 Camilla R. Shores,4 Kylie K. Hayase,2 Keun-Young Kim,3 Mark H. Ellisman,3 Oleg Alekseev,2 Marie E. Burns,5 and Vadim Y. Arshavsky2

1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

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1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

Find articles by Kim, K. in: PubMed | Google Scholar

1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

Find articles by Ellisman, M. in: PubMed | Google Scholar

1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

Find articles by Alekseev, O. in: PubMed | Google Scholar

1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

Find articles by Burns, M. in: PubMed | Google Scholar

1Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Ophthalmology, Duke University School of Medicine, Durham, United States of America

3National Center for Microscopy and Imaging Research, UCSD School of Medicine, La Jolla, United States of America

4Department of Cell Biology and Human Anatomy, UCD, Davis, United States of America

5Center for Neuroscience and Department of Ophthalmology & Vision Science, UCD, Davis, United States of America

Find articles by Arshavsky, V. in: PubMed | Google Scholar

Published February 5, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI196705.
Copyright © 2026, Lewis et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 5, 2026 - Version history
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Abstract

Vision begins in the outer segment compartment of photoreceptor cells, which is constantly renewed through the addition of membrane material at its base and ingestion of mature membranes at its tip by the retinal pigment epithelium (RPE). The close apposition of outer segments to the RPE is believed to be critical for maintaining this renewal process. Yet, in several retinal diseases, expansion of the subretinal space separating photoreceptors from the RPE does not immediately impact photoreceptor functionality. Here, we analyzed outer segment function and renewal in the Adam9 knockout mouse characterized by a major expansion of the subretinal space. Surprisingly, photoreceptor-RPE separation affected neither the sensitivity of photoreceptor light-responses nor the normal rate of outer segment renewal in this mouse prior to the onset of photoreceptor degeneration. The latter is achieved through the formation of elongated RPE “pseudopods” extending across the enlarged subretinal space to ingest outer segment tips. This work suggests that pseudopod formation may underlie the persistence of photoreceptor function in human diseases accompanied by photoreceptor-RPE separation, such as vitelliform macular dystrophy or age-related macular degeneration associated with subretinal drusenoid deposits.

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