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  • Original Paper
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Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells

Oncogene volume 21, pages 4635–4645 (2002)Cite this article

Abstract

The retinoblastoma suppressor gene product Rb has been assigned a critical role in cell cycle regulation, the induction of differentiation, and inhibition of oncogenic transformation. Inheritance of a mutant RB allele in humans is responsible for bilateral retinoblastoma, a malignant tumor of the retina. Trilateral retinoblastoma (TRB) is a rare variant of familial retinoblastoma in which, in addition to retinal tumors, tumors develop from the pineal gland, an organ ontologically related to the retina. Germline inactivation of Rb in mice leads to mid-gestational lethality with defects in erythropoeisis and neurogenesis. This embryonic lethality prohibits the analysis of Rb function in selected cell types at later stages of development or in the adult. Here, we describe the Cre-LoxP mediated somatic inactivation of Rb in a subset of neuroendocrine cells, including photoreceptor cells. We observed neuroendocrine tumors of the pineal and pituitary gland. These tumors invariably showed inactivation of Rb and Trp53. Remarkably, loss of Rb in photoreceptor cells does not lead to retinoblastoma or any phenotypic changes, not even when photoreceptor cells are made deficient in Rb, p107 and Trp53. Our results highlight the important differences that exist in tumor susceptibility between mice and man (e.g pineal gland) and question the photoreceptor cell origin of human retinoblastoma.

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Abbreviations

Retinoblastoma:

Rb

Interphotoreceptor Retinol Binding Protein:

IRBP

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Acknowledgements

We wish to thank B Wiggert (National Eye Institute, NIH, Bethesda, USA), T Shinohara (BWH, Harvard, Boston, USA) and A Parlow (NIDKD, NIH, Bethesda, USA) for antibodies and G Liou for the hIRBP promoter fragment (Medical College of Georgia, Augusta, USA). J Zevenhoven, D Hoogervorst, M Tjin-a-Koeng, K de Goeij and J Bulthuis for histo-technical assistance (Histology-core facility, NKI Amsterdam); N Bosnie, F van der Ahé, A Zwerver, T Maidment and S Greven for animal husbandry, and Jos Jonkers for the analysis of p53+/− mice. We thank E Danen, K Quon, S Ruiz and E Robanus-Maandag for useful comments on the manuscript. This work was supported through a program grant from the Netherlands Organization of Scientific Research (M Vooijs) and a grant from the Dutch Cancer Society (NKB/KWF to A Berns and M Vooijs).

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  1. Marc Vooijs

    Present address: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Box 8103, 660 S. Euclid Avenue, St. Louis, Missouri, 63110, MO, USA

Authors and Affiliations

  1. Division of Molecular Genetics, The Netherlands Cancer Institute., Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Marc Vooijs, Martin van der Valk & Anton Berns

  2. Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Hein te Riele

  3. Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Martin van der Valk

  4. Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, The Netherlands

    Anton Berns

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Correspondence to Anton Berns.

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Vooijs, M., te Riele, H., van der Valk, M. et al. Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells. Oncogene 21, 4635–4645 (2002). https://doi.org/10.1038/sj.onc.1205575

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