title: Rbpj cell autonomous regulation of retinal ganglion cell and cone photoreceptor fates in the mouse retina.
abstract: 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.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Riesenberg
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.forename: Nadean L
authors.initials: NL
authors.lastname: Brown
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D015785:Eye Diseases, Hereditary / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012160:Retina / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D017949:Retinal Cone Photoreceptor Cells / Q000145:classification / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D050820:Transcription Factor Brn-3B / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009419:Nerve Tissue Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012097:Repressor Proteins; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; C117638:Atoh7 protein, mouse; C487897:Helt protein, mouse; C499373:Notch3 protein, mouse; C085559:Pou4f2 protein, mouse; C497571:Rbpj protein, mouse; C088975:Vsx2 protein, mouse