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Nrl is required for rod photoreceptor development

Abstract

The protein neural retina leucine zipper (Nrl) is a basic motif–leucine zipper transcription factor that is preferentially expressed in rod photoreceptors1,2. It acts synergistically with Crx to regulate rhodopsin transcription3,4,5. Missense mutations in human NRL have been associated with autosomal dominant retinitis pigmentosa6,7. Here we report that deletion of Nrl in mice results in the complete loss of rod function and super-normal cone function, mediated by S cones. The photoreceptors in the Nrl−/− retina have cone-like nuclear morphology8 and short, sparse outer segments with abnormal disks. Analysis of retinal gene expression confirms the apparent functional transformation of rods into S cones in the Nrl−/− retina. On the basis of these findings, we postulate that Nrl acts as a 'molecular switch' during rod-cell development by directly modulating rod-specific genes while simultaneously inhibiting the S-cone pathway through the activation of Nr2e3.

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Figure 1: Targeted disruption of Nrl in mouse.
Figure 2: Electroretinography.
Figure 3: Light microscopy and ultrastructural analysis of retina.
Figure 4: Opsin immunohistochemistry.
Figure 5: Expression analysis of P10 mouse retina.
Figure 6: A model of photoreceptor differentiation in mice.

References

  1. Swaroop, A. et al. A conserved retina-specific gene encodes a basic motif/leucine zipper domain. Proc. Natl Acad. Sci. USA 89, 266–270 (1992).

    Article  CAS  Google Scholar 

  2. Swain, P.K. et al. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors. J. Biol. Chem. 276, 36824–36830 (2001).

    Article  CAS  Google Scholar 

  3. Rehemtulla, A. et al. The basic motif-leucine zipper transcription factor Nrl can positively regulate rhodopsin gene expression. Proc. Natl Acad. Sci. USA 93, 191–195 (1996).

    Article  CAS  Google Scholar 

  4. Chen, S. et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 19, 1017–1030 (1997).

    Article  CAS  Google Scholar 

  5. Mitton, K.P. et al. The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. J. Biol. Chem. 275, 29794–29799 (2000).

    Article  CAS  Google Scholar 

  6. Bessant, D.A. et al. A mutation in NRL is associated with autosomal dominant retinitis pigmentosa. Nature Genet. 21, 355–356 (1999).

    Article  CAS  Google Scholar 

  7. Martinez-Gimeno, M. et al. Mutations P51L and G122E in retinal transcription factor NRL associated with autosomal dominant and sporadic retinitis pigmentosa. Hum. Mutat. 17, 520 (2001).

    Article  CAS  Google Scholar 

  8. Carter-Dawson, L.D. & LaVail, M.M. Rods and cones in the mouse retina I. Structural analysis using light and electron microscopy. J. Comp. Neurol. 188, 245–262 (1979).

    Article  CAS  Google Scholar 

  9. Haider, N.B. et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nature Genet. 24, 127–131 (2000).

    Article  CAS  Google Scholar 

  10. Akhmedov, N.B. et al. A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl Acad. Sci. USA 97, 5551–5556 (2000).

    Article  CAS  Google Scholar 

  11. Furukawa, T., Morrow, E.M., Li, T., Davis, F.C. & Cepko, C.L. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nature Genet. 23, 466–470 (1999).

    Article  CAS  Google Scholar 

  12. Kobayashi, M. et al. Identification of a photoreceptor cell–specific nuclear receptor. Proc. Natl Acad. Sci. USA 96, 4814–4819 (1999).

    Article  CAS  Google Scholar 

  13. Haider, N.B., Naggert, J.K. & Nishina, P.M. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum. Mol. Genet. 10, 1619–1626 (2001).

    Article  CAS  Google Scholar 

  14. Kosaka, J., Suzuki, A., Morii, E. & Nomura, S. Differential localization and expression of α and β isoenzymes of protein kinase C in the rat retina. J. Neurosci. Res. 54, 655–663 (1998).

    Article  CAS  Google Scholar 

  15. Saari, J.C. et al. Cellular retinaldehyde-binding protein is expressed by oligodendrocytes in optic nerve and brain. Glia 21, 259–268 (1997).

    Article  CAS  Google Scholar 

  16. Zhao, X., Huang, J., Khani, S.C. & Palczewski, K. Molecular forms of human rhodopsin kinase (GRK1). J. Biol. Chem. 273, 5124–5131 (1998).

    Article  CAS  Google Scholar 

  17. Verderber, L., Johnson, W., Mucke, L. & Sarthy, V. Differential regulation of a glial fibrillary acidic protein-LacZ transgene in retinal astrocytes and Muller cells. Invest. Ophthalmol. Vis. Sci. 36, 1137–1143 (1995).

    CAS  PubMed  Google Scholar 

  18. Fan, W., Lin, N., Sheedlo, H.J. & Turner, J.E. Müller and RPE cell response to photoreceptor cell degeneration in aging Fischer rats. Exp. Eye. Res. 63, 9–18 (1996).

    Article  CAS  Google Scholar 

  19. Williams, D.S. Actin filaments and photoreceptor membrane turnover. BioEssays 13, 171–178 (1991).

    Article  Google Scholar 

  20. Cepko, C.L., Austin, C.P., Yang, X., Alexiades, M. & Ezzeddine, D. Cell fate determination in the vertebrate retina. Proc. Natl Acad. Sci. USA 93, 589–595 (1996).

    Article  CAS  Google Scholar 

  21. Cepko, C.L. The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr. Opin. Neurobiol. 9, 37–46 (1999).

    Article  CAS  Google Scholar 

  22. Livesey, F.J. & Cepko, C.L. Vertebrate neural cell-fate determination: lessons from the retina. Nature Rev. Neurosci. 2, 109–118 (2001).

    Article  CAS  Google Scholar 

  23. Harris, W.A. & Messersmith, S.L. Two cellular inductions involved in photoreceptor determination in the Xenopus retina. Neuron 9, 357–372 (1992).

    Article  CAS  Google Scholar 

  24. Tybulewicz, V.L.J., Crawford, C.E., Jackson, P.K., Bronson, P.T. & Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 (1991).

    Article  CAS  Google Scholar 

  25. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  Google Scholar 

  26. Kendall, S.K., Samuelson, L.C., Saunders, T.L., Wood, R.I. & Camper, S.A. Targeted disruption of the pituitary glycoprotein hormone α-subunit produces hypogonadal and hypothyroid mice. Genes Dev. 9, 2007–2019 (1995).

    Article  CAS  Google Scholar 

  27. Hitchcock, P.F. Morphology and distribution of synapses onto a type of large field ganglion cell in the retina of the goldfish. J. Comp. Neurol. 283, 177–188 (1989).

    Article  CAS  Google Scholar 

  28. Sambrook, J. & Russell, D.W. Molecular Cloning: A Laboratory Manual 3rd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001).

    Google Scholar 

  29. Coligan, J.E., Dunn, B.M., Ploegh, H.L., Speicher, D.W. & Wingfield, P.T. Current Protocols in Protein Science (John Wiley and Sons, 1999).

    Google Scholar 

  30. Toda, K., Bush, R.A., Humphries, P. & Sieving, P.A. The electroretinogram of the rhodopsin knock-out mouse. Vis. Neurosci. 16, 391–398 (1999).

    Article  CAS  Google Scholar 

  31. Ng, L. et al. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genet. 27, 94–98 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Akimoto, R. Farjo, P. Gillespie III, M. Gillett, S. Hiriyanna, B. Nelson, D. Sorenson, A. Tumath and M. Van Keuren for technical assistance. We are grateful to T. Glaser, P. Hitchcock and P. Raymond for comments on the manuscript. We acknowledge M. Applebury, R. Molday, J. Nathans and J. Saari for antibodies, C. Cepko, D. Deretic, S.G. Jacobson and D. Williams for constructive discussions and A. Nagy, R. Nagy and W. Abramow-Newerly for providing the R1 ES cells. This research was supported by grants from the National Institutes of Health [EY11115, EY07003], The Foundation Fighting Blindness, and Research to Prevent Blindness (RPB). A.S. is a recipient of a Lew R. Wasserman Merit Award from RPB.

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Correspondence to Anand Swaroop.

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Mears, A., Kondo, M., Swain, P. et al. Nrl is required for rod photoreceptor development. Nat Genet 29, 447–452 (2001). https://doi.org/10.1038/ng774

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