Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma.
Retinogenesis involves expansion of pluripotent progenitors, specification of postmitotic precursors, and terminal differentiation. Rb or Rb/p107 loss causes retinoblastoma in humans or mice, respectively. One model suggests that Rb- or Rb/p107-deficient retinal precursors have infinite proliferative capacity but are death-prone and must acquire an antiapoptotic mutation. Indeed, we show that Rb/p107 loss does not affect progenitor proliferation or precursor specification, but perturbs cell cycle exit in all seven retinal precursors. However, three precursors survive Rb/p107-loss and stop proliferating following terminal differentiation. Tumors arise from precursors that escape this delayed growth arrest. Thus, retinoblastoma arises from a precursor that has extended, not infinite, proliferative capacity, and is intrinsically death-resistant, not death-prone. We suggest that additional lesions common in retinoblastoma overcome growth arrest, not apoptosis.
Chen
Danian
D
Toronto Western Research Institute, University Health Network, Vision Science Research Program, Department of Ophthalmology and Visual Sciences, University of Toronto, 399 Bathurst Street, Toronto, Ontario, Canada, M5T 2S8.
Livne-bar
Izhar
I
Vanderluit
Jackie L
JL
Slack
Ruth S
RS
Agochiya
Mahima
M
Bremner
Rod
R
D025042:Amacrine Cells / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002454:Cell Differentiation; D002455:Cell Division; D005724:Ganglia / Q000378:metabolism; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107; D013234:Stem Cells / Q000378:metabolism
D009687:Nuclear Proteins; C493844:RBL1 protein, human; C489485:Rbl1 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107