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The Journal of Neuroscience, July 21, 2004, 24(29):6427-6436; doi:10.1523/JNEUROSCI.1335-04.2004

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Neurobiology of Disease
The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein

Qin Liu,¹ Jian Zuo,² and Eric A. Pierce¹

¹F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ²Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

The outer segments of rod and cone photoreceptor cells are highly specialized sensory cilia made up of hundreds of membrane discs stacked into an orderly array along the photoreceptor axoneme. It is not known how the alignment of the outer segment discs is controlled, although it has been suggested that the axoneme may play a role in this process. Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of retinitis pigmentosa (RP). Disruption of the Rp1 gene in mice causes misorientation of outer segment discs, suggesting a role for RP1 in outer segment organization. Here, we show that the RP1 protein is part of the photoreceptor axoneme. Amino acids 28-228 of RP1, which share limited homology with the microtubule-binding domains of the neuronal microtubule-associated protein (MAP) doublecortin, mediate the interaction between RP1 and microtubules, indicating that the putative doublecortin (DCX) domains in RP1 are functional. The N-terminal portion of RP1 stimulates the formation of microtubules in vitro and stabilizes cytoplasmic microtubules in heterologous cells. Evaluation of photoreceptor axonemes from mice with targeted disruptions of the Rp1 gene shows that Rp1 proteins that contain the DCX domains also help control axoneme length and stability in vivo. These results demonstrate that RP1 is a MAP. Given the specific expression of RP1 in photoreceptors, RP1 is thus the first photoreceptor-specific MAP to be identified. Furthermore, these findings indicate that the RP1 form of inherited retinal degeneration is part of the larger class of neurodegenerative diseases caused by MAP dysfunction.

Key words: axoneme; cilia; microtubule-associated proteins; outer segment; photoreceptor; retinitis pigmentosa

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Received April 8, 2004; revised June 7, 2004; accepted June 7, 2004.

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