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Julian Esteve-Rudd, Concepcion Lillo, David S. Williams; AMD-like Pathology in Klc1-/- Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4756.
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The phagocytosis and digestion of photoreceptor outer segment disk membranes is a major function of the RPE. We have tested whether kinesin-1 has a critical role in this process by studying retinas of mice lacking kinesin light chain 1 (KLC1).
Eyes were collected and processed for light and electron microscopy, and immunocytochemistry. Cryosections were labeled with antibodies against complement pathway markers, fibronectin and cathepsin D, and images obtained on a confocal microscope. Eyes for morphological and ultrastructural analysis were post-fixed in osmium tetroxide, dehydrated and embedded in epon resin. Some tissues were post-fixed in osmium-tannic acid-paraphenylenediamine (OTAP) to preserve neutral lipid composition.
Klc1 knock-out mice exhibited a loss of photoreceptors and choroidal neovascularization, particularly in the central retina. Bruch's membrane was thicker, mainly due to the accumulation of sub-RPE deposits and extensions of the inner collagen layer. Membranous debris and neutral lipid aggregates were observed among the basal deposits. This area also showed increased fibronectin labeling. The RPE cells exhibited aggregates of undigested phagosomes as well as accumulation of lysosomes, as indicated by cathepsin D labeling, in their cytoplasm. They also showed increased autofluorescence in frozen sections. C3 immunolabeling was significantly more intense along the basal side of RPE cells, and was higher in the central retina when compared to the periphery. C5b-9 immunolabeling was also detected in the choroid-RPE complex of mutant mice, suggesting activation of the complement terminal pathway.
Our studies indicate that impaired kinesin-1 function, due to lack of KLC1, results in AMD-like pathology. The indicated defective digestion of phagosomes suggests that kinesin-1 may function in the transport of phagosomes or lysosomes, and thus play an important role in phagosome maturation.
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