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involved in polar auxin transport? What are their interacting partners? Which signaling pathways do they participate in? Arriving at answers may help us to develop new elite varieties of rice.

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3. Jin, J. et al. Nat. Genet. 40, 1365–1369 (2008)4. Jones, J.W. & Acair, C.R. J. Hered. 28, 315–318

(1938).5. Li, P. et al. Cell Res. 17, 402–410 (2007).6. Yamazaki, Y. Bot. Mag. 98, 193–198 (1985).7. Abe, K. & Suge, H. J. Plant Res. 106, 337–343

(1993).8. Yoshihara, T. & Iino, M. Plant Cell Physiol. 48, 678–

688 (2007).9. Yu, B. et al. Plant J. 52, 891–898 (2007).

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(2006).13. Wang, H. et al. Nature 436, 714–719 (2005).14. Doebley, J., Stec, A. & Hubbard, L. Nature 386, 485–

488 (1997).15. Wang, E.T. et al. Nat. Genet. 40, 1370–1374

(2008).

nature genetics | volume 40 | number 11 | november 2008 1275

Photoreceptors in evolution and diseaseBoaz Cook & Andrew C Zelhof

a new study identifies the gene that, when mutated, causes autosomal recessive retinitis pigmentosa 25 (arRP25). The RP25 gene encodes an ortholog of Drosophila spacemaker (eyes shut), thus emphasizing common biological functions between Drosophila sensory systems and the human eye.

Retinal degeneration is caused by a diverse group of inherited syndromes that result in partial or complete blindness with an esti-mated prevalence of 1 in 3,500 (refs. 1,2). One of the most common types of degenera-tion is autosomal recessive retinitis pigmen-tosa (arRP). The genes associated with arRP identified to date, however, only account for a minority of affected individuals. On page 1285 of this issue, a new study by Abd El-Aziz et al.3 pinpoints the mutated gene at the RP25 locus, and shows that it is a potentially frequent cause of arRP. More importantly, the study highlights the commonality of molecular processes that take place in photoreceptors of distant species, as well as the use of evolutionarily conserved proteins to fulfill similar roles in diverse cell types (Fig. 1).

There are 26 associated arRP loci and for 21 the causative mutation has been identified; most of these mutations are responsible for a small percentage of cases (1–5%). In the course of recent studies, it became apparent that many different lineages from various geographical regions were all linked to the RP25 locus4–7, which may underlie a significant proportion of arRP. The availability of multiple pedigrees permitted a narrowing of the genetic interval, followed by the identification of a 100-kb dele-tion in all affected members of one family8. Subsequent characterization of the genomic interval revealed a single gene dispersed throughout approximately 2 Mb of DNA con-

sisting of 43 exons3. The final characterization of the RP25 locus identified 30 exons belonging to 9 annotated genes, 13 previously unreported

exons and approximately 1.2 kb of sequence that had not been incorporated into the final human genome assembly. Furthermore, deletions and

a

c

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IRS

Boaz Cook is in the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA. Andrew C. Zelhof is in the Department of Biology, Indiana University, Bloomington, Indiana 47405, USA. e-mail: bcook@scripps.edu or azelhof@indiana.edu

Figure 1 A comparison of Drosophila and human retinas. (a) The organization of a single Drosophila ommatidium. (b) A transmission electron micrograph cross-section through a single ommatidium. In Drosophila, spacemaker localizes to the inter-rhabdomeral space (IRS) that surrounds each of the rhabdomeres of the photoreceptor cells. (c) The organization of a human retina. RP25 localizes to the outer segment, which is located just below the layer of pigmented cells, in the region marked by horizontal lines. The critical role of spacemaker in maintaining cell shape and organ structure of Drosophila sensory systems suggests that in humans, RP25 provides mechanical support, rigidity and order necessary for the long-term integrity of the outer segment. Panels a and c are from Nat. Rev. Genet. 2, 846–857; 2001, and are reprinted with permission. Panel b is from Nature 443, 696–699; 2006, and is reprinted with permission.

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nonsense mutations within the transcript were found in all affected families. The sheer size of the locus (a large target for mutagenesis) would account for the diversity of ancestry groups affected by RP25.

The Drosophila orthologThe disease-associated gene at the RP25 locus encodes the human ortholog of Drosophila spacemaker (eyes shut)9,10. Spacemaker is a secreted extracellular matrix protein that is defined by two common features—a C termi-nus containing repeats of epidermal growth factor (EGF) domains interspersed with laminin G domains, and an N terminus con-sisting solely of EGF repeats. In Drosophila, spacemaker is critical for the creation of the inter-rhabdomeral space (IRS). The IRS is an extracellular compartment required for separation, shaping and positioning of the rhabdomeres, the homologous structures of vertebrate outer segments. The formation of extracellular space between photoreceptors (the IRS) was a critical step in insect evolu-tion, by which vision was improved by the use of the principle of neural superposition10.

In contrast to humans, the lack of space-maker (RP25) in Drosophila photoreceptor cells does not lead to retinal degeneration. The more general and likely conserved role of spacemaker was revealed in a genetic screen: flies lacking spacemaker showed temperature-sensitive uncoordination that resulted from an irreversible loss of mechanosensory responses. Succeeding experiments demonstrated that spacemaker localizes to the extracellular space of mechanosensory organs9,11 serving as a cellular ‘exoskeleton’11. Spacemaker pro-vides mechanical support to the sensory cell but still allows for specific movements of the cilia required for mechanotransduction. In mechanosensory neurons, the loss of space-maker leads to susceptibility of the interface

between the cell membrane and the extracel-lular space, resulting in irreversible structural damage caused by environmental stresses11.

Flies to humansWhat is the function of RP25 in human eyes? Given that spacemaker provides structural stability to sensory cells in Drosophila and seems to co-localize with rhodopsin in pho-toreceptor cells, it is tempting to postulate that RP25 provides rigidity and order to the outer segment of human photoreceptors. The degeneration observed in the absence of RP25 could be the end result of structural abnor-malities of the outer segment that accumu-late over time and that may be augmented by age-related factors. Testing such hypotheses has its difficulties, but it is possible to exploit an evolutionary quirk of spacemakers. The authors demonstrate that RP25 has been lost in multiple mammalian species, including mice. This absence provides an experimental platform where different forms of RP25 and/or RP25 interactors can be expressed onto a null background and their net effects stud-ied. As there is no apparent common feature between the eyes of species that have or do not have spacemaker proteins, at this time we cannot generate a plausible explanation for the gene loss. Identifying the factors that compensate for the absence of RP25 would improve our understanding of the degenera-tion process in general.

The parallels between Drosophila space-maker and human RP25 may extend to its functional interactions with other proteins. For example, what is required for the specific localization of RP25 to the outer segment? In Drosophila, spacemaker distribution is intri-cately linked to prominin10. In vertebrates, prominin-1 localizes to the outer segment of rod photoreceptor cells12 and mutation of the gene encoding prominin-1 in humans is

another causative agent of arRP and macu-lar degeneration12,13. As such, is prominin-1 responsible for the dispersal and localiza-tion of RP25? Do they act cooperatively to generate and maintain structural integrity of the membrane organization of the outer segment?

In the end, the identification of the gene for RP25 reveals what might be the genetic basis for a significant portion of arRP cases and thus paves the way for genetic counseling, pre-natal detection, and treatment. Furthermore, the marked similarities between the biology of spacemaker in Drosophila and in humans constitute a notable example of genetic and functional conservation in evolution, albeit in significantly different settings. Together, the identification of the RP25 mutations and the parallel role of spacemaker in Drosophila offer an invaluable entry point to understanding the disease mechanism, including the iden-tification of possible partners and molecular pathways, as well as the characterization of mechanical properties that RP25 confers.

1. Daiger, S.P., Bowne, S.J. & Sullivan, L.S. Arch. Ophthalmol. 125, 151–158 (2007).

2. Hartong, D.T., Berson, E.L. & Dryja, T.P. Lancet 368, 1795–1809 (2006).

3. Abd El-Aziz, M.M. et al. Nat. Genet. 40, 1285–1287 (2008).

4. Abd El-Aziz, M.M. et al. Ann. Hum. Genet. 71, 281–294 (2007).

5. Barragan, I., Marcos, I., Borrego, S. & Antinolo, G. Int. J. Mol. Med. 16, 1163–1167 (2005).

6. Khaliq, S. et al. Am. J. Hum. Genet. 65, 571–574 (1999).

7. Ruiz, A., Borrego, S., Marcos, I. & Antinolo, G.A. Am. J. Hum. Genet. 62, 1452–1459 (1998).

8. Abd El-Aziz, M.M. et al. Ann. Hum. Genet. 72, 463–477 (2008).

9. Husain, N. et al. Dev. Cell 11, 483–493 (2006). 10. Zelhof, A.C., Hardy, R.W., Becker, A. & Zuker, C.S.

Nature 443, 696–699 (2006). 11. Cook, B., Hardy, R.W., McConnaughey, W.B. & Zuker,

C.S. Nature 452, 361–364 (2008). 12. Maw, M.A. et al. Hum. Mol. Genet. 9, 27–34

(2000). 13. Yang, Z. et al. J. Clin. Invest. 118, 2908–2916

(2008).

1276 volume 40 | number 11 | november 2008 | nature genetics

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