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Analysis of Kinesin-2 Function in Photoreceptor Cells Using Synchronous Cre-loxP Knockout of Kif3a with RHO-Cre

¹From the Departments of Pharmacology, ²Neuroscience, and ⁶Cellular and Molecular Medicine, and the ⁷Howard Hughes Medical Institute, University of California San Diego (UCSD) School of Medicine, La Jolla, California; and the ⁴F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

PURPOSE. To determine the relationship between the presence of kinesin-2 and photoreceptor cell viability and opsin transport, by generating RHO-Cre transgenic mice and breeding them to mice with a floxed kinesin-2 motor gene.

METHODS. Different lines of RHO-Cre transgenic mice were generated and characterized by transgene expression, histology, and electrophysiology. Mice from one line, showing uniform transgene expression, were crossed with Kif3a^flox/Kif3a^flox mice. The time courses of photoreceptor Cre expression, KIF3A loss, ectopic opsin accumulation, and photoreceptor cell death were determined by Western blot analysis and microscopy.

RESULTS. One of the RHO-Cre lines effected synchronous expression of Cre and thus uniform excision of Kif3a^flox in rod photoreceptors across the retina. After the neonatal production of CRE and the initiation of KIF3A loss, ectopic accumulation of opsin was detected by postnatal day (P)7, and ensuing photoreceptor cell death was evident after P10 and almost complete by P28. Of importance, the photoreceptor cilium formed normally, and the disc membranes of the nascent outer segment remained normal until P10.

CONCLUSIONS. The RHO-Cre-8 mice provide an improved tool for studying gene ablation in rod photoreceptor cells. Regarding kinesin-2 function in photoreceptor cells, the relatively precise timing of events after CRE excision of Kif3a^flox allows us to conclude that ectopic opsin is a primary cellular lesion of KIF3A loss, consistent with the hypothesis that opsin is a cargo of kinesin-2. Moreover, it demonstrates that KIF3A loss results in very rapid photoreceptor cell degeneration.

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