title: The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties.
abstract: OBJECTIVE
  Human retinoblastoma arises from an undefined developing retinal cell after inactivation of RB1. This is emulated in a murine retinoblastoma model by inactivation of pRB by retinal-specific expression of simian virus 40 large T-antigen (TAg-RB). Some mutational events after RB1 loss in humans are recapitulated at the expression level in TAg-RB, supporting preclinical evidence that this model is useful for comparative studies between mouse and human. Here, the characteristics of the TAg-RB cell of origin are defined.
  
  
  METHODS
  TAg-RB mice were killed at ages from embryonic day (E)18 to postnatal day (P)35. Tumors were analyzed by immunostaining, DNA copy number PCR, or real-time quantitative RT-PCR for TAg protein, retinal cell type markers, and retinoblastoma-relevant genes.
  
  
  RESULTS
  TAg expression began at P8 in a row of inner nuclear layer cells that increased in number through P21 to P28, when clusters reminiscent of small tumors emerged from cells that escaped a wave of apoptosis. Early TAg-expressing cells coexpressed the developmental marker Chx10 and glial markers CRALBP, clusterin, and carbonic anhydrase II (Car2), but not TuJ1, an early neuronal marker. Emerging tumors retained expression of only Chx10 and carbonic anhydrase II. As with human retinoblastoma, TAg-RB tumors showed decreased Cdh11 DNA copy number and gain of Kif14 and Mycn. It was confirmed that TAg-RB tumors lose expression of tumor suppressor cadherin-11 and overexpress oncogenes Kif14, Dek, and E2f3.
  
  
  CONCLUSIONS
  TAg-RB tumors displayed molecular similarity to human retinoblastoma and origin in a cell with features of differentiated Müller glia with progenitor properties.
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Sanja
authors.initials: S
authors.lastname: Pajovic
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
authors.forename: Clarellen
authors.initials: C
authors.lastname: Spencer
authors.forename: Helen
authors.initials: H
authors.lastname: Dimaras
authors.forename: Marija
authors.initials: M
authors.lastname: Orlic-Milacic
authors.forename: Mellone N
authors.initials: MN
authors.lastname: Marchong
authors.forename: Kwong-Him
authors.initials: KH
authors.lastname: To
authors.forename: Brigitte
authors.initials: B
authors.lastname: Thériault
authors.forename: Mark
authors.initials: M
authors.lastname: Auspitz
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Gallie
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D017209:Apoptosis; D014408:Biomarkers, Tumor; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology*; D019572:Retinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000235:genetics; D014404:Tubulin / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; D014404:Tubulin; C462941:beta3 tubulin, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3