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Retinopathy and attenuated circadian entrainment in Crx-deficient mice

Nature Genetics volume 23, pages 466–470 (1999)Cite this article

Abstract

Crx, an Otx-like homeobox gene, is expressed specifically in the photoreceptors of the retina and the pinealocytes of the pineal gland1,2. Crx has been proposed to have a role in the regulation of photoreceptor-specific genes in the eye and of pineal-specific genes in the pineal gland. Mutations in human CRX are associated with the retinal diseases, cone-rod dystrophy-2 (adCRD2; refs 3, 4, 5), retinitis pigmentosa5 (RP) and Leber congenital amaurosis5,6 (LCA), which all lead to loss of vision. We generated mice carrying a targeted disruption of Crx. Crx–/– mice do not elaborate photoreceptor outer segments and lacked rod and cone activity as assayed by electroretinogram (ERG). Expression of several photoreceptor- and pineal-specific genes was reduced in Crx mutants. Circadian entrainment was also affected in Crx–/– mice.

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Figure 1: Targeted mutation at the Crx locus.
Figure 2: Retinal histology of Crx mutant mice.
Figure 3: Phenotypes of Crx-mutant mice at 1–6 months.
Figure 4: Levels of expression of photoreceptor-specific genes in Crx mutant retina.
Figure 5: Pineal gland of Crx-mutant mice.
Figure 6: Effect of Crx genotype on photoentrainment in mice.

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References

  1. Furukawa, T., Morrow, E.M. & Cepko, C.L. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91, 531–541 (1997).

    Article  CAS  Google Scholar 

  2. 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 

  3. Freund, C.L. et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91, 543–553 ( 1997).

    Article  CAS  Google Scholar 

  4. Swain, P.K. et al. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 19, 1329–1336 (1997).

    Article  CAS  Google Scholar 

  5. Sohocki, M.M. et al. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am. J. Hum. Genet. 63, 1307–1315 (1998).

    Article  CAS  Google Scholar 

  6. Freund, C.L. et al. De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nature Genet. 18, 311–312 (1998).

    Article  CAS  Google Scholar 

  7. Li, X. et al. A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX. Proc. Natl Acad. Sci. USA 95, 1876–1881 (1998).

    Article  CAS  Google Scholar 

  8. Blackshaw, S. & Snyder, S.H. Developmental expression pattern of phototransduction components in mammalian pineal implies a light-sensing function. J. Neurosci. 17, 8074– 8082 (1997).

    Article  CAS  Google Scholar 

  9. Humphries, M.H. et al. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genet. 15, 216– 219 (1997).

    Article  CAS  Google Scholar 

  10. Sanyal, S. & Jansen, H.G. Absence of receptor outer segments in the retina of rds mutant mice. Neurosci Lett. 21 , 23–26 (1981).

    Article  CAS  Google Scholar 

  11. Reuter, J.H. & Sanyal, S. Development and degeneration of retina in rds mutant mice: the electroretinogram. Neurosci. Lett. 48, 231–237 (1984).

    Article  CAS  Google Scholar 

  12. Liou, G.I. et al. Retina-specific expression from the IRBP promoter in transgenic mice is conferred by 212 bp of the 5-'flanking region. Biochem. Biophys. Res. Commun. 181, 159–165 (1991).

    Article  CAS  Google Scholar 

  13. Boatright, J.H. et al. A major cis activator of the IRBP gene contains CRX-binding and Ret-1/PCE-I elements. Mol. Vis. 3, 15 (1997).

    CAS  PubMed  Google Scholar 

  14. Bovolenta, P., Mallamaci, A., Briata, P., Corte, G. & Boncinelli, E. Implication of OTX2 in pigment epithelium determination and neural retina differentiation. J. Neurosci. 17, 4243–4252 (1997).

    Article  CAS  Google Scholar 

  15. Foxman, S.G., Heckenlively, J.R., Bateman, J.B. & Wirtschafter, J.D. Classification of congenital and early onset retinitis pigmentosa. Arch. Ophthalmol. 103, 1502–1506 (1985).

    Article  CAS  Google Scholar 

  16. Foster, R.G. Shedding light on the biological clock. Neuron 20, 829–832 (1998).

    Article  CAS  Google Scholar 

  17. Provencio, I., Jiang, G., De Grip, W.J., Hayes, W.P. & Rollag, M.D. Melanopsin: an opsin in melanophores, brain, and eye. Proc. Natl Acad. Sci. USA 95, 340– 345 (1998).

    Article  CAS  Google Scholar 

  18. Sun, H., Gilbert, D.J., Copeland, N.G., Jenkins, N.A. & Nathans, J. Peropsin, a novel visual pigment-like protein located in the apical microvilli of the retinal pigment epithelium. Proc. Natl Acad. Sci. USA 94, 9893– 9898 (1997).

    Article  CAS  Google Scholar 

  19. Soni, B.G., Philp, A.R., Foster, R.G. & Knox, B.E. Novel retinal photoreceptors. Nature 394, 27–28 (1998).

    Article  CAS  Google Scholar 

  20. Lucas, R.J., Freedman, M.S., Munoz, M., Garcia-Fernandez, J.M. & Foster, R.G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 (1999).

    Article  CAS  Google Scholar 

  21. Freedman, M.S. et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284, 502– 504 (1999).

    Article  CAS  Google Scholar 

  22. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).

    Article  CAS  Google Scholar 

  23. Li, T. et al. Effect of vitamin A supplementation on rhodopsin mutants threonine-17→methionine and proline-347→serine in transgenic mice and in cell cultures. Proc. Natl Acad. Sci. USA 95, 11933– 11938 (1998).

    Article  CAS  Google Scholar 

  24. Grosse, J. & Davis, F.C. Melatonin entrains the restored circadian activity rhuthms of syrian hamsters bearing fetal suprachiasmatic nucleus grafts. J. Neurosci. 18, 8032– 8037 (1998).

    Article  CAS  Google Scholar 

  25. Goldberg, A.F. & Molday, R.S. Defective subunit assembly underlies a digenic form of retinitis pigmentosa linked to mutations in peripherin/rds and rom-1. Proc. Natl Acad. Sci. USA 93, 13726–13730 (1996).

    Article  CAS  Google Scholar 

  26. Sun, H. & Nathans, J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. Nature Genet. 17, 15–16 (1997).

    Article  Google Scholar 

  27. Morrow, E.M., Furukawa, T., Lee, J.E. & Cepko, C.L. NeuroD regulates cell fate determination in the developing neural retina. Development 126, 23–36 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank P. Leder and C. Doherty for helping us generate mutant mice; E. Raviola and S. Ito for advice on light and electron microscopy of retinal sections; J. Nathans and T. Shinohara for cDNAs encoding mouse cone opsin (blue, green/red) and rod arrestin, respectively; and S. Fields-Berry, J. Zitz, M. Samson and H. Regan for technical assistance. This work was supported by the Howard Hughes Medical Institute.

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  1. Takahisa Furukawa

    Present address: Center for Developmental Biology, The University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, USA

Authors and Affiliations

  1. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    Takahisa Furukawa, Eric M. Morrow & Constance L. Cepko

  2. The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary , Boston, Massachusetts, USA

    Tiansen Li

  3. Department of Biology, Northeastern University, Boston, Massachusetts, USA

    Fred C. Davis

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  1. Takahisa Furukawa
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  5. Constance L. Cepko
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Correspondence to Takahisa Furukawa or Constance L. Cepko.

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Furukawa, T., Morrow, E., Li, T. et al. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat Genet 23, 466–470 (1999). https://doi.org/10.1038/70591

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