Abstract
X-linked retinitis pigmentosa 2 (XLRP2) patients and Rp2null mice exhibit severe cone photoreceptor degeneration. However, due to the paucity of cones in mammalian model systems, it is not clear how cones respond to the loss of RP2. Here we have used the Nrl-/- mice, which develop a rodless and short wavelength (S) opsin-containing cone-only retina, to generate Rp2null::Nrl-/- double knock out (Rp2-DKO) mice. We found that the ciliary axoneme and the outer segments (OSs) of the cones were significantly longer with disorganized membrane infoldings as compared to the Nrl-/- mice. Additionally, we found misregulation in the expression of the genes related to ophthalmic disease, cell trafficking, and stress-response in the Rp2-DKO mice prior to the onset of cone degeneration. Surprisingly, the loss of RP2 did not affect progressive photoreceptor dysfunction of the Nrl-/- mice and the trafficking of S opsin. Our data suggest that RP2 is a negative regulator of cone OS length but does not affect S-opsin trafficking and S-cone function. Our studies also provide a cone-only platform to design cone-targeted therapeutic strategies for X-linked RP2.
Highlights
Cilia are evolutionarily conserved microtubule-based antennae involved in regulating a myriad of cellular signaling cascades (Singla and Reiter, 2006; Gerdes et al, 2009)
We previously showed that the deletion of the retinal ciliopathy protein retinitis pigmentosa 2 (RP2) (Schwahn et al, 1998) results in hyperelongation of the ciliary microtubules and defective outer segments (OSs) structure and function of M-opsin expressing cones but not rod photoreceptors in mice (Li et al, 2013, 2015)
We previously showed that the ablation of Rp2 in mice (Rp2null) results in cone OS extension and progressive cone dysfunction (Li et al, 2015)
Summary
Cilia are evolutionarily conserved microtubule-based antennae involved in regulating a myriad of cellular signaling cascades (Singla and Reiter, 2006; Gerdes et al, 2009). During cilia formation, the basal body (mother centriole) docks at the apical plasma membrane and initiates the nucleation of ciliary microtubules in the form of transition zone and distal axoneme (Inglis et al, 2006). The machinery involved in the generation of the photosensory cilia is conserved, the photoreceptors develop an elaborate distal cilium in the form of multiple membranous disks loaded with billions of opsin molecules and lipids involved in the phototransduction cascade (Rosenbaum et al, 1999; Rosenbaum and Witman, 2002; Besharse et al, 2003; Pazour and Witman, 2003; Insinna et al, 2009; Kennedy and Malicki, 2009). Even subtle defects in the formation or function of the photoreceptor cilia are associated with retinal degenerative diseases (Besharse et al, 2003; Anand and Khanna, 2012; Deretic and Wang, 2012; Yildiz and Khanna, 2012).
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