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The transcription factor Nr2e3 functions in retinal progenitors to suppress cone cell generation

Published online by Cambridge University Press:  30 January 2007

NEENA B. HAIDER,
PAUL DEMARCO,
ARNE M. NYSTUEN,
XIAONA HUANG,
RICHARD S. SMITH,
MAUREEN A. MCCALL,
JÜRGEN K. NAGGERT and
PATSY M. NISHINA
NEENA B. HAIDER
Affiliation:
Departments of Genetics, Cell Biology, Anatomy and Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NebraskaThe Jackson Laboratory, Bar Harbor, Maine
PAUL DEMARCO
Affiliation:
Departments of Psychological & Brain Sciences and Ophthalmology & Visual Sciences, University of Louisville, Louisville, KentuckyLouisville VA Medical Center, Louisville, Kentucky
ARNE M. NYSTUEN
Affiliation:
Departments of Genetics, Cell Biology, Anatomy and Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
XIAONA HUANG
Affiliation:
Departments of Genetics, Cell Biology, Anatomy and Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
RICHARD S. SMITH
Affiliation:
The Jackson Laboratory, Bar Harbor, Maine
MAUREEN A. MCCALL
Affiliation:
Departments of Psychological & Brain Sciences and Ophthalmology & Visual Sciences, University of Louisville, Louisville, Kentucky
JÜRGEN K. NAGGERT
Affiliation:
The Jackson Laboratory, Bar Harbor, Maine
PATSY M. NISHINA
Affiliation:
The Jackson Laboratory, Bar Harbor, Maine
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Abstract

The transcription factor Nr2e3 is an essential component for development and specification of rod and cone photoreceptors; however, the mechanism through which it acts is not well understood. In this study, we use Nr2e3rd7/rd7 mice that harbor a mutation in Nr2e3, to serve as a model for the human retinal disease Enhanced S Cone Syndrome. Our studies reveal that NR2E3 is expressed in late retinal progenitors and differentiating photoreceptors of the developing retina and localized to the cell bodies of mature rods and cones. In particular, we demonstrate that the abnormal increase in cone photoreceptors observed in Nr2e3rd7/rd7 mice arise from ectopic mitotic progenitor cells that are present in the outer nuclear layer of the mature Nr2e3rd7/rd7 retina. A prolonged phase of proliferation is observed followed by abnormal retinal lamination with fragmented and disorganized photoreceptor synapses that result in a progressive loss of rod and cone function. An extended and pronounced wave of apoptosis is also detected at P30 and temporally correlates with the phase of prolonged proliferation. Approximately twice as many apoptotic cells were detected compared to proliferating cells. This wave of apoptosis appears to affect both rod and cone cells and thus may account for the concurrent loss of rod and cone function. We further show that Nr2e3rd7/rd7 cones do not express rod specific genes and Nr2e3rd7/rd7 rods do not express cone specific genes. Our studies suggest that, based on its temporal and spatial expression, NR2E3 acts simultaneously in different cell types: in late mitotic progenitors, newly differentiating post mitotic cells, and mature rods and cones. In particular, this study reveals the function of NR2E3 in mitotic progenitors is to repress the cone generation program. NR2E3 is thus one of the few genes known to influence the competency of retinal progenitors while simultaneously directing the rod and cone differentiation.

Keywords

Nr2e3Cell proliferationPhotoreceptorsRetinal developmentRetinal progenitors

Information

Type
Research Article
Information
Visual Neuroscience , Volume 23 , Issue 6 , November 2006, pp. 917 - 929
Copyright
© 2006 Cambridge University Press

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References

REFERENCES

Akhmedov, N.B., Piriev, N.I., Chang, B., Rappoport, A.L., Hawes, N.L., Nishina, P.M., Nusinowitz, S., Heckenlively, J.R., Roderick, T.H., Kozak, C.A., Dancinger, M., Davisson, M.T., & Farber, D.B. (2001). A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proceedings of the National Academy of Science USA 97, 5551–5556.Google Scholar
Applebury, M.L., Antoch, M.P., Baxter, L.C., Chun, L.L., Falk, J.D., Farhangfar, F., Kage, K., Krzystolik, M.G., Lyass, L.A., & Robbins, J.T. (2000). The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning. Neuron 27, 513–523.CrossRefGoogle Scholar
Carter-Dawson, L.D. & LaVail, M.M. (1979). Rods and cones in the mouse retina. Journal of Comparative Neurology 188, 263–272.CrossRefGoogle Scholar
Cayouette, M., Barres, B.A., & Raff, M. (2003). Importance of intrinsic mechanisms in cell fate decisions in the developing rat retina. Neuron 40, 897–904.CrossRefGoogle Scholar
Chan, W.Y., Lorke, D.E., Tiu, S.C., & Yew, D.T. (2002). Proliferation and apoptosis in the developing human neocortex. The Anatomical Record 267, 473–477.Google Scholar
Chen, J., Rattner, A., & Nathans, J. (2005). The rod photoreceptor-specific nuclear receptor Nr2e3 suppresses transcription of multiple cone-specific genes. Journal of Neuroscience 25, 118–129.Google Scholar
Cheng, H., Aleman, T.S., Cideciyan, A.V., Khanna, R., Jacobson, S.G., & Swaroop, A. (2006). In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development. Human Molecular Genetics 15, 2588–2602.CrossRefGoogle Scholar
Corbo, J.C. & Cepko, C.L. (2005). A hybrid photoreceptor expressing both rod and cone genes in a mouse model of Enhanced S-Cone Syndrome. PLoS Genetics 1, e11.CrossRefGoogle Scholar
Cunningham, J.J., Levine, E.M., Zindy, F., Golobeva, O., Roussel, M.F., & Smeyne, R.J. (2002). The cyclin-dependent kinase inhibitors p19 (Ink4d) and p27 (Kip1) are co-expressed in select retinal cells and act cooperatively to control cell cycle exit. Molecular and Cellular Neuroscience 19, 359–374.CrossRefGoogle Scholar
Curcio, C.A., Sloan, K.R., Kalina, R.E., & Hendrickson, A.E. (1990). Human photoreceptor topogoraphy. Journal of Comparative Neurology 292, 497–523.CrossRefGoogle Scholar
Donovan, S.L. & Dyer, M.A. (2004). Developmental defects in Rb-deficient retina. Vision Research 44, 3323–3333.CrossRefGoogle Scholar
Dyer, M.A. & Cepko, C.L. (2000). Control of Müller glial cell proliferation and activation following retinal injury. Nature Neuroscience 3, 873–880.Google Scholar
Dyer, M.A. & Cepko, C.L. (2001). p27kip1 and p57kip2 regulate proliferation in distinct retinal progenitor cell populations. Journal of Neuroscience 21, 4259–4271.Google Scholar
Fei, Y. (2003). Development of the cone photoreceptor mosaic in the mouse retina revealed by fluorescent cones in transgenic mice. Molecular Vision 9, 31–42.Google Scholar
Freund, C.L., Gregory-Evans, C.Y., Furukawa, T., Papaioannou, M., Looser, J., Ploder, L., Bellingham, J., Ng, D., Herbrick, J.A., Duncan, A., Scherer, S.W., Tsui, L.C., Loutradis-Anagnostou, A., Jacobson, S.G., Cepko, C.L., Bhattacharya, S.S., & McInnes, R.R. (1997). Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91, 543–553.CrossRefGoogle Scholar
Furukawa, T., Morrow, E.M., & Cepko, C.L. (1997). Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91, 531–541.CrossRefGoogle Scholar
Haider, N.B., Jacobson, S.G., Cideciyan, A.V., Swideski, R., Streb, L.M., Searby, C., Beck, G., Hockey, R., Hanna, D.B., Gorman, S., Duhl, D., Carmi, R., Bennet, J., Weleber, R.G., Fishman, G.A., Wright, A.F., Stone, E.M., & Sheffield, V.C. (2000). Mutation of a nuclear receptor gene, NR2E3, causes enhanced s cone syndrome, a disorder of retinal cell fate. Nature Genetics 24, 127–131.CrossRefGoogle Scholar
Haider, N.B., Naggert, J.K., & Nishina, P.M. (2001). Excess cone cell proliferation due to lack of a functional NR2E23 causes retinal dysplasia and degeneration in rd7/rd7 mice. Human Molecular Genetics 10, 1619–1626.CrossRefGoogle Scholar
Hong, C., Khanna, H., Oh, E.C.T., Hicks, D., Mitton, K.P., & Swaroop, A. (2004). Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Human Molecular Genetics 13, 1563–1575.Google Scholar
Hood, D.C., Cideciyan, A.V., Roman, A.J., & Jacobson, S.G. (1995). Enhanced S cone syndrome: Evidence for an abnormally large number of S cones. Vision Research 35, 1473–1481.CrossRefGoogle Scholar
Jacobson, S.G., Marmor, M.F., Kemp, C.M., & Knighton, R.W. (1990). SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Investigative Ophthalmology and Visual Science 31, 827–838.Google Scholar
Jacobson, S.G., Romman, M.I., Gass, J.D.M., & Parker, J.A. (1991). Relatively enhanced S cone function in the Goldmann-Favre Syndrome. American Journal of Ophthalmology 111, 446–453.CrossRefGoogle Scholar
Jacobson, S.G., Sumaroka, A., Aleman, T.S., Cideciyan, A.V., Schwartz, S.B., Roman, A.J., McInnes, R.R., Sheffield, V.C., Stone, E.M., Swaroop, A., & Wright, A.F. (2004). Nuclear receptor NR2E32 gene mutations distort human retinal laminar architecture and cause an unusual degeneration. Human Molecular Genetics 13, 1893–1902.CrossRefGoogle Scholar
Levine, E.M., Close, J., Fero, M., Ostrovsky, A., & Reh, T.A. (2000). p27kip1 regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Developmental Biology 219, 299–314.CrossRefGoogle Scholar
Livesey, F.L. & Cepko, C.L. (2001). Vertebrate neural cell-fate determination: lessons from the retina. Nature Reviews–Neuroscience 2, 109–118.CrossRefGoogle Scholar
Marmor, M.F., Jacobson, S.G., Forester, M.H., Kellner, U., & Weleber, R.G. (1990). Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. American Journal of Ophthalmology 110, 124–134.CrossRefGoogle Scholar
Mears, A.J., Kondo, M., Swain, P.K., Takada, Y., Bush, R.A., Saunders, T.L., Sieving, P.A., & Swaroop, A. (2001). Nrl is required for rod photoreceptor development. Nature Genetics 29, 447–452.CrossRefGoogle Scholar
Milam, A.H., Rose, L., Cideciyan, A.V., Barakat, M.R., Tang, W.X., Gupta, N., Aleman, T.S., Wright, A.F., Stone, E.M., Sheffield, V.C., & Jacobson, S.G. (2002). The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proceedings of the National Academy of Science USA 99, 473–478.CrossRefGoogle Scholar
Nathans, J., Merbs, S.L., Sung, C.H., Weitz, C.J., & Wang, Y. (1992). Molecular genetics of human visual pigments. Annual Review of Genetics 26, 403–424.CrossRefGoogle Scholar
Ng, L., Hurley, J.B., Dierks, B., Srinivas, M., Salto, C., Vennstrom, B., Reh, T.A., & Forrest, D. (2001). A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genetics 27, 94–98.Google Scholar
Nishida, A., Furukawa, A., Koike, C., Tano, Y., Aizawa, S., Matsuo, I., & Furukawa, T. (2003). Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nature Neuroscience 6, 1255–1263.CrossRefGoogle Scholar
Nguyen, M.D., Mushynski, W.E., & Julien, J.P. (2002). Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death and Differentiation 9, 1294–1306.CrossRefGoogle Scholar
Peng, G.H., Ahmad, O., Ahmad, F., Liu, J., & Chen, S. (2005). The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Human Molecular Genetics 15, 747–764.CrossRefGoogle Scholar
Rich, K.A., Zhan, Y., & Blanks, J.C. (1997). Migration and synaptogenesis of cone photoreceptors in the developing mouse retina. Journal of Comparative Neurology 388, 47–63.3.0.CO;2-O>CrossRefGoogle Scholar
Weishaupt, J.H., Neusch, C., & Bahr, M. (2003). Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell and Tissue Research 312, 1–8.Google Scholar
Wood, K.A., Dipasquale, B., & Youle, R.J. (1993). In situ labeling of granule cells for apoptosis-associated DNA fragmentation reveals different mechanisms of cell loss in developing cerebellum. Neuron 11, 621–632.CrossRefGoogle Scholar
Young, R.W. (1985a). Cell differentiation in the retina of the mouse. The Anatomical Record 212, 199–205.Google Scholar
Young, R.W. (1985b). Cell proliferation during postnatal development of the retina in the mouse. Developmental Brain Research 21, 229–239.Google Scholar
Zeiss, C.J. & Johnson, E.A. (2004). Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd-1 mouse. Investigative Ophthalmology Visual Science 45, 971–976.CrossRefGoogle Scholar
Zhang, J., Gray, J., Wu, L., Leone, G., Rowan, S., Cepko, C.L., Zhu, X., Craft, C.M., & Dyer, M.A. (2004). Rb regulates proliferation and rod photoreceptor in the mouse retina. Nature Genetics 36, 351–360.CrossRefGoogle Scholar
Zhu, X. & Craft, C.M. (2000). Modulation of CRX transactivation activity by phosducin isoforms. Molecular and Cellular Bioloy 20, 5216–5226.CrossRefGoogle Scholar