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Richard J. Nuckels, Anthony Ng, Tristan Darland, Jeffrey M. Gross; The Vacuolar-ATPase Complex Regulates Retinoblast Proliferation and Survival, Photoreceptor Morphogenesis, and Pigmentation in the Zebrafish Eye. Invest. Ophthalmol. Vis. Sci. 2009;50(2):893-905. doi: 10.1167/iovs.08-2743.
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purpose. The vacuolar (v)-ATPase complex is a key regulator of the acidification of endosomes, lysosomes, and the luminal compartments of several cell types, tissues, and organs; however, little is know about the in vivo function of the v-ATPase complex or its roles during eye development. This study was conducted to characterize ocular defects in five zebrafish mutants in which core components of the v-ATPase complex were affected (atp6v1h, atp6v1f, atp6v1e1, atp6v0c, and atp6v0d1), as well as a sixth mutant in which a v-ATPase associated protein (atp6ap1) was affected.
methods. v-ATPase mutant zebrafish were characterized by histologic, molecular, and ultrastructural analyses.
results. v-ATPase mutant zebrafish were oculocutaneous albinos and presented with defects in the formation and/or survival of melanosomes and with malformations in the retinal pigmented epithelium (RPE) that compromised melanosome distribution. They were microphthalmic, and BrdU incorporation assays indicated that retinoblast cell cycle exit and sustained proliferation in the ciliary marginal zone (CMZ) were compromised. v-ATPase mutants also possessed elevated levels of apoptotic neurons within their retinas and brains. Photoreceptor outer segment morphology was abnormal in the mutant eye with rosette structures forming adjacent to the affected regions of the RPE. Ultrastructural analyses indicate that RPE cells in v-ATPase mutants possess numerous membrane-bounded vacuoles containing undigested outer segment material. In situ hybridization analyses localized v-ATPase subunit transcripts within the RPE.
conclusions. These results demonstrate that the v-ATPase complex plays several critical roles during vertebrate eye development and maintenance, and they suggest that defects in v-ATPase complex function could possibly underlie human ocular disorders that affect the RPE.
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