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W. Baehr, C. B. Watt, D. S. Williams, Y. Z. Le, S. Li, C.-K. Chen, J. M. Frederick, P. Avasthi; Heterotrimeric Kinesin-2 is Required for Trafficking of Membrane Proteins to Cone, but Not Rod, Outer Segments. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4797.
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© ARVO (1962-2015); The Authors (2016-present)
Kinesin-2 is an anterograde molecular motor localized to the connecting cilium and axoneme of mammalian photoreceptors. The role of kinesin-2 in anterograde intraflagellar transport (IFT) was examined by photoreceptor-specific deletions of KIF3A, its obligatory motor subunit.
Rod- and cone-specific deletions of KIF3A were generated by mating floxed Kif3a mice with iCre75 transgenic mice expressing Cre recombinase in rods, or with Hrgp-Cre mice expressing Cre in cones, respectively. Rod and cone knockout retinas were analyzed by RT-PCR, immunocytochemistry, immunoblotting, ERG and electron microscopy.
In P28 central cones lacking KIF3A, phototransduction proteins (cone pigments, T, PDE6, CNGA3, GRK1, ARR4, GC1, GCAP1, Prom1) did not traffic to the outer segments, resulting in complete absence of a photopic ERG and progressive cone degeneration. Connecting cilia and axoneme fine structure appeared comparable to littermate controls at P13, although mutant cone outer segments revealed various states of membrane disorganization. Rod photoreceptors lacking KIF3A degenerated rapidly following P14. However, phototransduction components including rhodopsin, T, PDE6, CNGA1, GRK1, R9AP and Prom1 trafficked normally to the outer segments during the entire course of degeneration. Peripherin/rds trafficked normally to KIF3A-deleted rod and cone outer segments. Further, we show that KIF3A deletion did not affect anterograde trafficking of synaptic proteins (bassoon, ribeye, PSD95, UNC119 and complexins III and IV) in mutant rods or cones.
Our results demonstrate that kinesin II powers anterograde IFT in cone, but not rod, photoreceptors even though rods and cones share similar structures and closely related or identical phototransduction polypeptides. The identities of the anterograde IFT motor in rods, or of anterograde motors transporting membrane proteins to the synaptic terminals, are unknown.
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