Abstract
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 3rd 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.
Highlights
A new N-ethyl-N-nitrosourea (ENU)-induced mouse recessive mutation, identified by fundus examination of the eye, develops depigmented patches, indicating retinal disorder
At 4 weeks of age, there is no significant difference in outer nuclear layers (ONL) thickness between the r15 heterozygous and homozygous mice (p . 0.5); significantly reduced ONL thickness was observed in 6-month old (p, 0.05, except the 22 mm data point) and 18-month old homozygous (p, 0.001) mutant mice compared to the heterozygous controls
This work demonstrates that NHE8 is essential for the survival of photoreceptor cells, and it plays an important role for the polarity and function of retinal pigment epithelium (RPE) cells
Summary
A new N-ethyl-N-nitrosourea (ENU)-induced mouse recessive mutation, identified by fundus examination of the eye, develops depigmented patches, indicating retinal disorder. We have further generated NHE8 knockout mice and confirmed similar phenotypes, including abnormal RPE cells and late-onset photoreceptor cell loss. The fundamental molecular and cellular mechanisms that regulate and maintain life-long function of the RPE and photoreceptor cells are still not well understood[6]. Understanding these mechanisms is critical for elucidating the events that trigger pathological cascades towards photoreceptor cell death, which occurs in human eye diseases such as retinitis pigmentosa (RP) and AMD5,7,8. Our current work suggests that NHE8 is essential for the survival of photoreceptor cells and plays an important role in the retina by regulating RPE cell polarity and function
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