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Nrl is required for rod photoreceptor development

Nature Genetics volume 29, pages 447–452 (2001)Cite this article

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.

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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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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, 48105, Michigan, USA

    Alan J. Mears, Mineo Kondo, Prabodha K. Swain, Yuichiro Takada, Ronald A. Bush, Paul A. Sieving & Anand Swaroop

  2. Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, 466-8550, Japan

    Mineo Kondo

  3. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Thomas L. Saunders & Anand Swaroop

  4. National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA

    Paul A. Sieving

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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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