Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina

Abstract

Retinal progenitor cells regulate their proliferation during development so that the correct number of each cell type is made at the appropriate time. We found that the homeodomain protein Prox1 regulates the exit of progenitor cells from the cell cycle in the embryonic mouse retina. Cells lacking Prox1 are less likely to stop dividing, and ectopic expression of Prox1 forces progenitor cells to exit the cell cycle. During retinogenesis, Prox1 can be detected in differentiating horizontal, bipolar and AII amacrine cells. Horizontal cells are absent in retinae of Prox1−/− mice and misexpression of Prox1 in postnatal progenitor cells promotes horizontal-cell formation. Thus, Prox1 activity is both necessary and sufficient for progenitor-cell proliferation and cell-fate determination in the vertebrate retina.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Temporal expression and distribution of Prox1 in mammalian retinae during development.
Figure 2: Prox1 is turned on and off in proliferating retinal progenitor cells.
Figure 3: Proliferation of progenitor cells is altered in Prox1−/− retinae.
Figure 4: Ectopic expression of Prox1.

Similar content being viewed by others

References

  1. Wassle, H., Grunert, U. & Rohrenbeck, J. Immunocytochemical staining of AII-amacrine cells in the rat retina with antibodies against parvalbumin. J. Comp. Neurol. 332, 407–420 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Clancy, B., Darlington, R.B. & Finlay, B.L. Translating developmental time across mammalian species. Neuroscience 105, 7–17 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  PubMed Central  Google Scholar 

  4. Alexiades, M.R. & Cepko, C. Quantitative analysis of proliferation and cell cycle length during development of the rat retina. Dev. Dyn. 205, 293–307 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Wigle, J.T., Chowdhury, K., Gruss, P. & Oliver, G. Prox1 function is crucial for mouse lens-fibre elongation. Nat. Genet. 21, 318–322 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Dyer, M.A. & Cepko, C.L. The p57(Kip2) cyclin kinase inhibitor is expressed by a restricted set of amacrine cells in the rodent retina. J. Comp. Neurol. 429, 601–614 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Dyer, M.A. & Cepko, C.L. p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations. J. Neurosci. 21, 4259–4271 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dyer, M.A. & Cepko, C.L. p57(Kip2) regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina. Development 127, 3593–3605 (2000).

    CAS  PubMed  Google Scholar 

  10. Hatakeyama, J., Tomita, K., Inoue, T. & Kageyama, R. Roles of homeobox and bHLH genes in specification of a retinal cell type. Development 128, 1313–1322 (2001).

    CAS  PubMed  Google Scholar 

  11. Burmeister, M. et al. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat. Genet. 12, 376–384 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Brown, N.L. et al. Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis. Development 125, 4821–4833 (1998).

    CAS  PubMed  Google Scholar 

  13. Brown, N.L., Patel, S., Brzezinski, J. & Glaser, T. Math5 is required for retinal ganglion cell and optic nerve formation. Development 128, 2497–2508 (2001).

    CAS  PubMed  Google Scholar 

  14. Wang, S.W. et al. Requirement for Math5 in the development of retinal ganglion cells. Genes Dev. 15, 24–29 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kay, J.N., Finger-Baier, K.C., Roeser, T., Staub, W. & Baier, H. Retinal ganglion cell genesis requires lakritz, a Zebrafish atonal Homolog. Neuron 30, 725–736 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Molday, R.S. & MacKenzie, D. Monoclonal antibodies to rhodopsin: characterization, cross-reactivity, and application as structural probes. Biochemistry 22, 653–660 (1983).

    Article  CAS  PubMed  Google Scholar 

  17. De Leeuw, A.M., Gaur, V.P., Saari, J.C. & Milam, A.H. Immunolocalization of cellular retinol-, retinaldehyde- and retinoic acid-binding proteins in rat retina during pre- and postnatal development. J. Neurocytol. 19, 253–264 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Morrow, E.M., Belliveau, M.J. & Cepko, C.L. Two phases of rod photoreceptor differentiation during rat retinal development. J. Neurosci. 18, 3738–3748 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fields-Berry, S.C., Halliday, A.L. & Cepko, C.L. A recombinant retrovirus encoding alkaline phosphatase confirms clonal boundary assignment in lineage analysis of murine retina. Proc. Natl. Acad. Sci. USA 89, 693–697 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Turner, D.L. & Cepko, C.L. A common progenitor for neurons and glia persists in rat retina late in development. Nature 328, 131–136 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Livesey, F.J., Furukawa, T., Steffen, M.A., Church, G.M. & Cepko, C.L. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx. Curr. Biol. 10, 301–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Tusher, V.G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M.H. Baron for helpful discussions and support; Z. Burke, J. Wigle and N. Harvey for maintaining the Prox1-mutant mice; J. Zhang and W. Liu for assistance with immunostainings and dissections; C. Craft for antibody against cone arrestin; R. Yung for technical assistance with microarray screening; and A. McArthur for editing of the manuscript. This work was supported in part by the Charles H. Revson Fellowship for Biomedical Sciences (to M.A.D.); US National Institutes of Health grants (to C.L.C and G.O.), Cancer Center Support; and the American Lebanese Syrian Associated Charities.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Constance L. Cepko or Guillermo Oliver.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dyer, M., Livesey, F., Cepko, C. et al. Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 34, 53–58 (2003). https://doi.org/10.1038/ng1144

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1144

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing