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Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development

Nature Neuroscience volume 6, pages 1255–1263 (2003)Cite this article

Abstract

Understanding the molecular mechanisms by which distinct cell fate is determined during organogenesis is a central issue in development and disease. Here, using conditional gene ablation in mice, we show that the transcription factor Otx2 is essential for retinal photoreceptor cell fate determination and development of the pineal gland. Otx2-deficiency converted differentiating photoreceptor cells to amacrine-like neurons and led to a total lack of pinealocytes in the pineal gland. We also found that Otx2 transactivates the cone-rod homeobox gene Crx, which is required for terminal differentiation and maintenance of photoreceptor cells. Furthermore, retroviral gene transfer of Otx2 steers retinal progenitor cells toward becoming photoreceptors. Thus, Otx2 is a key regulatory gene for the cell fate determination of retinal photoreceptor cells. Our results reveal the key molecular steps required for photoreceptor cell-fate determination and pinealocyte development.

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Figure 1: Comparison of Otx2 and Crx expression in mouse retina.
Figure 2: Generation of Crx-cre transgenic mice and Otx2 conditional knockout mice.
Figure 3: Otx2 is required for photoreceptor development.
Figure 4: Otx2 regulates Crx expression.
Figure 5: OTX2 induces retinal progenitors to photoreceptor cell fate.
Figure 6: Immunostaning with amacrine-subpopulation markers.
Figure 7: Otx2 CKO retina becomes degenerative.

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Acknowledgements

We thank J. Miyazaki for the CAG-CAT-Z mice; R.S. Molday for the anti-rhodopsin antibody; K.Rajewsky for the Cre plasmid; P.V. Lippincott, A. Tani, T. Nakane, M. Murai and H. Yoshii for technical assistance; L.F. Parada, J.M. Graff, M. Henkemeyer and J. Jiang for their encouragement. This work was supported by Precursory Research for Embryonic Science and Technology (PRESTO), Dynamics of Development systems and Advanced Brain Science, Grant-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Young Scientists (B).

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Authors and Affiliations

  1. Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, 565-0874, Osaka, Japan

    Akihiro Nishida, Akiko Furukawa, Chieko Koike & Takahisa Furukawa

  2. Department of Ophthalmology, Osaka University Medical School, Yamadaoka, Suita, 565-0871, Osaka, Japan

    Akiko Furukawa & Yasuo Tano

  3. Center for Developmental Biology, RIKEN, Chuo-ku, 650-0047, Kobe, Japan

    Shinichi Aizawa & Isao Matsuo

  4. PRESTO, Japan Science and Technology Corporation, Hon-cho 4-1-8, Kawaguchi, Saitama, Japan

    Takahisa Furukawa

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Correspondence to Takahisa Furukawa.

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Supplementary information

Supplementary Fig. 1.

A model for photoreceptor development and gene regulation. (a) Otx2 expression begins at a stage of priming of the photoreceptor cell fate. At a stage of fixation, Otx2 upregulates Crx, and once Crx is induced, it upregulates itself by autoregulation. Terminal differentiation occurs through upregulation of various photoreceptor-specific genes by Crx and possibly Otx2. (b) A part of common progenitor cells exits the cell cycle and chooses the photoreceptor lineage. Otx2 fixes the pre-committed precursors to the committed photoreceptor precursor status. If Otx2 is ablated before fixing to the committed status, the pre-committed precursors are induced to die or affected to change their cell fate into amacrine neurons. Crx induces terminal differentiation of the committed photoreceptor precursors into mature rods and cones. (PDF 255 kb)

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Nishida, A., Furukawa, A., Koike, C. et al. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat Neurosci 6, 1255–1263 (2003). https://doi.org/10.1038/nn1155

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