Mouse Slc9a8 Mutants Exhibit Retinal Defects Due to Retinal Pigmented Epithelium Dysfunction
Open accessAbstract
PURPOSE: As part of a large scale systematic screen to determine the effects of gene knockout mutations in mice, a retinal phenotype was found in mice lacking the Slc9a8 gene, encoding the sodium/hydrogen ion exchange protein NHE8. We aimed to characterize the mutant phenotype and the role of sodium/hydrogen ion exchange in retinal function. METHODS: Detailed histology characterized the pathological consequences of Slc9a8 mutation, and retinal function was assessed by electroretinography (ERG). A conditional allele was used to identify the cells in which NHE8 function is critical for retinal function, and mutant cells analyzed for the effect of the mutation on endosomes. RESULTS: Histology of mutant retinas reveals a separation of photoreceptors from the RPE and infiltration by macrophages. There is a small reduction in photoreceptor length and a mislocalization of visual pigments. The ERG testing reveals a deficit in rod and cone pathway function. The RPE shows abnormal morphology, and mutation of Slc9a8 in only RPE cells recapitulates the mutant phenotype. The NHE8 protein localizes to endosomes, and mutant cells have much smaller recycling endosomes. CONCLUSIONS: The NHE8 protein is required in the RPE to maintain correct regulation of endosomal volume and/or pH which is essential for the cellular integrity and subsequent function of RPE.
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RPE lacking NHE8 have abnormally small recycling endosomes, and mice with an RPE-specific deletion of Slc9a8 show widespread retinal and RPE degeneration.
“RPE lacking NHE8 have abnormally small recycling endosomes, and mice with an RPE-specific deletion of Slc9a8 show widespread retinal and RPE degeneration (Jadeja et al., 2015; Xia et al., 2015, 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Jadeja et al., 2015
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Cites
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
A global double-fluorescent Cre reporter mouse
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L., & Luo, L. (2007) · genesis · doi:10.1002/dvg.20335 · Cited by 3,491 · see citing works
A conditional knockout resource for the genome-wide study of mouse gene function
Skarnes, W. C., Rosen, B., West, A. P., Koutsourakis, M., Bushell, W., Iyer, V., Mujica, A. O., Thomas, M., Harrow, J., Cox, T., et al. (2011) · Nature · doi:10.1038/nature10163 · Cited by 1,708 · see citing works
Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger
Schultheis, P. J., Clarke, L. L., Meneton, P., Miller, M. L., Soleimani, M., Gawenis, L. R., Riddle, T. M., Duffy, J., Doetschman, T., Wang, T., et al. (1998) · Nature Genetics · doi:10.1038/969 · Cited by 863 · see citing works
Identification of the gene responsible for Best macular dystrophy
Petrukhin, K. E., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andréasson, S., et al. (1998) · Nature Genetics · doi:10.1038/915 · Cited by 688 · see citing works
Mattapallil, M. J., Wawrousek, E. F., Chan, C.-C., Zhao, H., Roychoudhury, J., Ferguson, T. A., & Caspi, R. R. (2012) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.12-9662 · Cited by 678 · see citing works
Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes.
White, J. K., Gerdin, A.-K., Karp, N. A., Ryder, E., Buljan, M., Bussell, J. N., Salisbury, J., Clare, S., Ingham, N. J., Podrini, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.022 · Cited by 509 · see citing works
Self-citationMarquardt, A. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.9.1517 · Cited by 362 · see citing works
Brett, C. L., Tukaye, D. N., Mukherjee, S., & Rao, R. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-11-0999 · Cited by 294 · see citing works
SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers
Donowitz, M., Tse, C., & Fuster, D. G. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.05.001 · Cited by 275 · see citing works
Sodium/Hydrogen Exchanger Gene Defect in Slow-Wave Epilepsy Mutant Mice
Cox, G. A., Lutz, C. M., Yang, C., Biemesderfer, D., Bronson, R. T., Fu, A. Q., Aronson, P. S., Noebels, J. L., & Frankel, W. N. (1997) · Cell · doi:10.1016/s0092-8674(01)80016-7 · Cited by 263 · see citing works
Schultheis, P. J., Clarke, L. L., Meneton, P., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1249 · Cited by 252 · see citing works
Gibbs, D., Kitamoto, J., & Williams, D. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1130432100 · Cited by 250 · see citing works
Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures
Bell, S. M., Schreiner, C. M., Schultheis, P. J., Miller, M. L., Evans, R. L., Vorhees, C. V., Shull, G. E., & Scott, W. J. (1999) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1999.276.4.c788 · Cited by 234 · see citing works
Krämer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L. A., Rivera, A., Rudolph, G., Kellner, U., Andrassi-Darida, M., Lorenz, B., et al. (2000) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200447 · Cited by 217 · see citing works
Renal expression of novel Na+/H+exchanger isoform NHE8
Goyal, S., Heuvel, G. B. V., & Aronson, P. S. (2003) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00352.2002 · Cited by 185 · see citing works
Wallace, H. A. C., Marques-Kranc, F., Richardson, M., Luna-Crespo, F., Sharpe, J. A., Hughes, J. R., Wood, W. G., Higgs, D. R., & Smith, A. J. H. (2007) · Cell · doi:10.1016/j.cell.2006.11.044 · Cited by 164 · see citing works
Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., & Morrow, E. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.043 · Cited by 147 · see citing works
Cre‐mediated recombination in the skin melanocyte lineage
Delmas, V., Martinozzi, S., Bourgeois, Y., Holzenberger, M., & Larue, L. (2003) · genesis · doi:10.1002/gene.10197 · Cited by 140 · see citing works
Long-range downstream enhancers are essential for Pax6 expression
Kleinjan, D. A., Seawright, A., Mella, S., Carr, C. B., Tyas, D. A., Simpson, T. I., Mason, J. O., Price, D. J., & van Heyningen, V. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.060 · Cited by 136 · see citing works
Human CRB1 -Associated Retinal Degeneration: Comparison with the rd8 Crb1 -Mutant Mouse Model
Alemán, T. S., Cideciyan, A. V., Aguirre, G. K., Huang, W., Mullins, C. L., Román, A. J., Sumaroka, A., Olivares, M. B., Tsai, F. F., Schwartz, S., et al. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-7701 · Cited by 116 · see citing works
Longbottom, R., Fruttiger, M., Douglas, R. H., Martinez-Barbera, J. P., Greenwood, J., & Moss, S. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902593106 · Cited by 85 · see citing works
Impaired Gastric Acid Secretion in Mice with a Targeted Disruption of the NHE4 Na+/H+ Exchanger
Gawenis, L. R., Greeb, J., Prasad, V., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414118200 · Cited by 84 · see citing works
Kao, L., Kurtz, L. M., Shao, X. M., Papadopoulos, M. C., Liu, L., Bok, D., Nusinowitz, S., Chen, B., Stella, S., Andre, M., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.249961 · Cited by 75 · see citing works
The Sodium/Proton Exchanger NHE8 Regulates Late Endosomal Morphology and Function
Lawrence, S. P., Bright, N. A., Luzio, J. P., & Bowers, K. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-12-1053 · Cited by 62 · see citing works
Ontogeny of NHE8 in the rat proximal tubule
Becker, A. M., Zhang, J., Goyal, S., et al. (2007) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00400.2006 · Cited by 61 · see citing works
Yu, K., Qu, Z., Cui, Y., et al. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-0301 · Cited by 57 · see citing works
Thrombospondin-1 (TSP1)–Null and TSP2-Null Mice Exhibit Lower Intraocular Pressures
Haddadin, R. I., Oh, D., Kang, M. H., Villarreal, G., Kang, J.-H., Jin, R., Gong, H., & Rhee, D. J. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-9013 · Cited by 55 · see citing works
Impaired mucin synthesis and bicarbonate secretion in the colon of NHE8 knockout mice
Xu, H. J., Zhang, B., Li, J., Wang, C., Chen, H., & Ghishan, F. K. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00146.2012 · Cited by 53 · see citing works
NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion
Liu, C., Xu, H. J., Zhang, B., et al. (2013) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00101.2013 · Cited by 45 · see citing works
Inhibitors of NHE-1 Na+/H+ exchange reduce mouse intraocular pressure.
Avila, M. Y., Seidler, R. W., Stone, R. A., et al. (2002) · PubMed · Cited by 43 · see citing works
NHE8 plays important roles in gastric mucosal protection
Xu, H. J., Li, J., Chen, H., et al. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00433.2012 · Cited by 34 · see citing works
Disruption of NHE8 expression impairs Leydig cell function in the testes
Xu, H. J., Chen, H., Li, J., Zhao, Y., & Ghishan, F. K. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00289.2014 · Cited by 28 · see citing works
Loss of NHE8 expression impairs ocular surface function in mice
Xu, H. J., Zhao, Y., Li, J., et al. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00296.2014 · Cited by 17 · see citing works
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The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
- Authors
- Jadeja, S., Barnard, A. R., McKie, L., Cross, S. H., White, J. K., Robertson, M., Budd, P. S., MacLaren, R. E., & Jackson, I. J.
- Affiliations
- Institute of Genetics and Cancer (GB)
- John Radcliffe Hospital (GB)
- Wellcome Sanger Institute (GB)
- Roslin Institute (GB)
- Corresponding author
- Jackson, Ian J.
- ORCID
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2015-05-13
- Volume
- 56
- Issue
- 5
- Pages
- 3015
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC4538965
- OpenAlex
- W2121047727
- Cited by
- 13
- References
- 34
- Citations by year
- 2023: 1 · 2022: 2 · 2020: 4 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (079643)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- NHE8, retinal pigment epithelium, retinal dysfunction, photoreceptor degeneration, endosomal pH, recycling endosomes, macrophage infiltration, conditional knockout, retinal histopathology
- MeSH terms
- Animals, Disease Models, Animal, Electroretinography, Fluorescent Antibody Technique, Intraocular Pressure, Mice, Inbred C57BL, Mutation, Ophthalmoscopy, Plasmids, Retinal Diseases, Sodium-Hydrogen Exchangers, Microscopy, Confocal, Cell Culture Techniques, Gene Silencing, Mice, Retinal Pigment Epithelium, Gene Knockout Techniques, Real-Time Polymerase Chain Reaction
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