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The Journal of Neuroscience, October 14, 2009, 29(41):12865-12877; doi:10.1523/JNEUROSCI.3382-09.2009

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Development/Plasticity/Repair
Rbpj Cell Autonomous Regulation of Retinal Ganglion Cell and Cone Photoreceptor Fates in the Mouse Retina

Amy N. Riesenberg,¹ Zhenyi Liu,^2,3 Raphael Kopan,^2,3 and Nadean L. Brown¹

¹Division of Developmental Biology, Cincinnati Children's Research Foundation, and Departments of Pediatrics and Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, and ²Department of Developmental Biology and ³Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Nadean L. Brown, Division of Developmental Biology, Cincinnati Children's Research Foundation, ML 7007, 3333 Burnet Avenue, Cincinnati, OH 45229. Email: nadean.brown{at}cchmc.org

Vertebrate retinal progenitor cells (RPCs) are pluripotent, but pass through competence states that progressively restrict their developmental potential (Cepko et al., 1996; Livesey and Cepko, 2001; Cayouette et al., 2006). In the rodent eye, seven retinal cell classes differentiate in overlapping waves, with RGCs, cone photoreceptors, horizontals, and amacrines forming predominantly before birth, and rod photoreceptors, bipolars, and Müller glia differentiating postnatally. Both intrinsic and extrinsic factors regulate each retinal cell type (for review, see Livesey and Cepko, 2001). Here, we conditionally deleted the transcription factor Rbpj, a critical integrator of multiple Notch signals (Jarriault et al., 1995; Honjo, 1996; Kato et al., 1997; Han et al., 2002), during prenatal mouse retinal neurogenesis. Removal of Rbpj caused reduced proliferation, premature neuronal differentiation, apoptosis, and profound mispatterning. To determine the cell autonomous requirements for Rbpj during RGC and cone formation, we marked Cre-generated retinal lineages with GFP expression, which showed that Rbpj autonomously promotes RPC mitotic activity, and suppresses RGC and cone fates. In addition, the progressive loss of Rbpj–/– RPCs resulted in a diminished progenitor pool available for rod photoreceptor formation. This circumstance, along with the overproduction of Rbpj–/– cones, revealed that photoreceptor development is under homeostatic regulation. Finally, to understand how the Notch pathway regulates the simultaneous formation of multiple cell types, we compared the RGC and cone phenotypes of Rbpj to Notch1 (Jadhav et al., 2006b; Yaron et al., 2006), Notch3, and Hes1 mutants. We found particular combinations of Notch pathway genes regulate the development of each retinal cell type.

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Received July 14, 2009; revised Aug. 17, 2009; accepted Aug. 20, 2009.

Correspondence should be addressed to Nadean L. Brown, Division of Developmental Biology, Cincinnati Children's Research Foundation, ML 7007, 3333 Burnet Avenue, Cincinnati, OH 45229. Email: nadean.brown{at}cchmc.org

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