NHE8 is essential for RPE cell polarity and photoreceptor survival
Open accessAbstract
A new N-ethyl-N-nitrosourea (ENU)-induced mouse recessive mutation, identified by fundus examination of the eye, develops depigmented patches, indicating retinal disorder. Histology data show aberrant retinal pigment epithelium (RPE) and late-onset photoreceptor cell loss in the mutant retina. Chromosomal mapping and DNA sequencing reveal a point mutation (T to A) of the Slc9a8 gene, resulting in mutant sodium/proton exchanger 8 (NHE8)-M120K protein. The lysine substitution decreases the probability of forming the 3(rd) transmembrane helix, which impairs the pore structure of the Na(+)/H(+) exchanger. Various RPE defects, including mislocalization of the apical marker ezrin, and disrupted apical microvilli and basal infoldings are observed in mutant mice. We have further generated NHE8 knockout mice and confirmed similar phenotypes, including abnormal RPE cells and late-onset photoreceptor cell loss. Both in vivo and in vitro data indicate that NHE8 co-localizes with ER, Golgi and intracellular vesicles in RPE cells. Thus, NHE8 function is necessary for the survival of photoreceptor cells and NHE8 is important for RPE cell polarity and function. Dysfunctional RPE may ultimately lead to photoreceptor cell death in the NHE8 mutants. Further studies will be needed to elucidate whether or not NHE8 regulates pH homeostasis in the protein secretory pathways 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 Xia et al., 2015
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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
- Xia, C.-H., Liu, H., Cheung, D., Tang, F., Chang, B., Li, M., & Gong, X.
- Affiliations
- University of California, Berkeley (US)
- Jackson Laboratory (US)
- Corresponding author
- Xia, Chun-hong
- Gong, Xiaohua
- Venue
- Scientific Reports
- Published
- 2015-03-20
- Volume
- 5
- Issue
- 1
- Pages
- 9358-9358
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4366848
- OpenAlex
- W2037427739
- Cited by
- 12
- References
- 46
- Citations by year
- 2022: 2 · 2021: 3 · 2020: 3 · 2018: 3 · 2017: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- University of Michigan
- National Institutes of Health (5r01ey019943-13, EY003176, EY013849)
- National Eye Institute (R01-EY019943, R01EY013849, P30EY003176)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- NHE8, retinal pigment epithelium, photoreceptor cell death, recessive mutations, apical microvilli, Na+/H+ exchanger, pH homeostasis
- MeSH terms
- Animals, Mutation, Cell Polarity, Sodium-Hydrogen Exchangers, Photoreceptor Cells, Vertebrate, Mice, Retinal Pigment Epithelium
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