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The Journal of Neuroscience, August 5, 2009, 29(31):9748-9760; doi:10.1523/JNEUROSCI.5854-08.2009

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Neurobiology of Disease
Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa

Tetsuji Yamashita,^1 * Jiewu Liu,^1 * Jiangang Gao,¹ Sean LeNoue,¹ Changguan Wang,² Jack Kaminoh,² Sara J. Bowne,³ Lori S. Sullivan,³ Stephen P. Daiger,³ Kang Zhang,² Malinda E. C. Fitzgerald,^4,5 Vladimir J. Kefalov,⁶ and Jian Zuo¹

¹Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, ²John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah 84132, ³Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, ⁴Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee 38163, ⁵Christian Brothers University, Memphis, Tennessee 38104, and ⁶Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Jian Zuo, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. Email: jian.zuo{at}stjude.org

Retinitis pigmentosa 1 (RP1) is a common inherited retinopathy with variable onset and severity. The RP1 gene encodes a photoreceptor-specific, microtubule-associated ciliary protein containing the doublecortin (DCX) domain. Here we show that another photoreceptor-specific Rp1-like protein (Rp1L1) in mice is also localized to the axoneme of outer segments (OSs) and connecting cilia in rod photoreceptors, overlapping with Rp1. Rp1L1–/– mice display scattered OS disorganization, reduced electroretinogram amplitudes, and progressive photoreceptor degeneration, less severe and slower than in Rp1–/– mice. In single rods of Rp1L1–/–, photosensitivity is reduced, similar to that of Rp1–/–. While individual heterozygotes are normal, double heterozygotes of Rp1 and Rp1L1 exhibit abnormal OS morphology and reduced single rod photosensitivity and dark currents. The electroretinogram amplitudes of double heterozygotes are more reduced than those of individual heterozygotes combined. In support, Rp1L1 interacts with Rp1 in transfected cells and in retina pull-down experiments. Interestingly, phototransduction kinetics are normal in single rods and whole retinas of individual or double Rp1 and Rp1L1 mutant mice. Together, Rp1 and Rp1L1 play essential and synergistic roles in affecting photosensitivity and OS morphogenesis of rod photoreceptors. Our findings suggest that mutations in RP1L1 could underlie retinopathy or modify RP1 disease expression in humans.

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Received Dec. 7, 2008; revised June 1, 2009; accepted June 22, 2009.

Correspondence should be addressed to Jian Zuo, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. Email: jian.zuo{at}stjude.org

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