Mosaic deletion of Rb arrests rod differentiation and stimulates ectopic synaptogenesis in the mouse retina.
The retinoblastoma gene (Rb) regulates neural progenitor cell proliferation and cell fate specification and differentiation. For the developing mouse retina, two distinct functions of Rb have been described: regulation of retinal progenitor cell proliferation and rod photoreceptor development. Cells that would normally become rods fail to mature and remain as immature cells in the outer nuclear layer in the adult. By using Chx10-Cre;Rb(Lox/-) mice, we generated a chimeric retina with alternating apical-basal stripes of wild-type and Rb-deficient tissue. This provides a unique model with which to study synaptogenesis at the outer plexiform layer within regions that lack differentiated rods. In regions where rods failed to differentiate, the outer plexiform layer (OPL) was disrupted. Horizontal cells formed, and their somata were appropriately aligned, but their neurites did not project laterally. Instead many horizonal cell neurites extended apically, forming ectopic synapses with photoreceptors at all levels of the outer nuclear layer. These ectopic photoreceptor terminals contained synaptic ribbons, horizontal cell processes with synaptic vesicles, and a single mitochrondrion characteristic of rod spherules. Rb-deficient bipolar cells differentiated normally, extended dendrites to the OPL, and formed synapses that were indistinguishable from adjacent wild-type cells. In contrast to OPL-positioned synapses, ectopic synapses did not contain bipolar dendrites. This finding suggests that horizontal cells and photoreceptors can form stable synapses that are devoid of bipolar dendrites outside the normal boundaries of the OPL. Finally, analysis of P4, P7, P12, and P15 retinae suggests that the apical horizontal cell processes result from their failure to establish their normal lateral projections during development.
Johnson
Dianna A
DA
Department of Ophthalmology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
Donovan
Stacy L
SL
Dyer
Michael A
MA
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics*; D002678:Chimera / Q000002:abnormalities / Q000254:growth & development; D002828:Choristoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000002:abnormalities* / Q000254:growth & development / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000473:pathology / Q000648:ultrastructure; D051245:Retinal Bipolar Cells / Q000473:pathology / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000002:abnormalities* / Q000254:growth & development / Q000648:ultrastructure; D016160:Retinoblastoma Protein / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013569:Synapses / Q000473:pathology* / Q000648:ultrastructure
D016160:Retinoblastoma Protein