The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated müller glia with progenitor properties

Sanja Pajovic, Timothy Corson, Clarellen Spencer, Helen Dimaras, Marija Orlic-Milacic, Mellone N. Marchong, Kwong Him To, Brigitte Thèriault, Mark Auspitz, Brenda L. Gallie

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Purpose. 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.

Original languageEnglish
Pages (from-to)7618-7624
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number10
DOIs
StatePublished - Sep 2011

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Retinoblastoma
Neuroglia
Neoplasms
Carbonic Anhydrase II
Clusterin
Retinoblastoma Genes
Simian virus 40
Viral Tumor Antigens
DNA
Oncogenes
Real-Time Polymerase Chain Reaction
Apoptosis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated müller glia with progenitor properties. / Pajovic, Sanja; Corson, Timothy; Spencer, Clarellen; Dimaras, Helen; Orlic-Milacic, Marija; Marchong, Mellone N.; To, Kwong Him; Thèriault, Brigitte; Auspitz, Mark; Gallie, Brenda L.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 10, 09.2011, p. 7618-7624.

Research output: Contribution to journalArticle

Pajovic, S, Corson, T, Spencer, C, Dimaras, H, Orlic-Milacic, M, Marchong, MN, To, KH, Thèriault, B, Auspitz, M & Gallie, BL 2011, 'The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated müller glia with progenitor properties', Investigative Ophthalmology and Visual Science, vol. 52, no. 10, pp. 7618-7624. https://doi.org/10.1167/iovs.11-7989
Pajovic, Sanja ; Corson, Timothy ; Spencer, Clarellen ; Dimaras, Helen ; Orlic-Milacic, Marija ; Marchong, Mellone N. ; To, Kwong Him ; Thèriault, Brigitte ; Auspitz, Mark ; Gallie, Brenda L. / The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated müller glia with progenitor properties. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 10. pp. 7618-7624.
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abstract = "Purpose. 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 M{\"u}ller glia with progenitor properties.",
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T1 - The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated müller glia with progenitor properties

AU - Pajovic, Sanja

AU - Corson, Timothy

AU - Spencer, Clarellen

AU - Dimaras, Helen

AU - Orlic-Milacic, Marija

AU - Marchong, Mellone N.

AU - To, Kwong Him

AU - Thèriault, Brigitte

AU - Auspitz, Mark

AU - Gallie, Brenda L.

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N2 - Purpose. 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.

AB - Purpose. 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.

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