Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells.
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.
Vooijs
Marc
M
Division of Molecular Genetics, The Netherlands Cancer Institute. Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. vooijsm@pcg.wustl.edu
te Riele
Hein
H
van der Valk
Martin
M
Berns
Anton
A
D000483:Alleles; D000818:Animals; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D005136:Eye Proteins; D017353:Gene Deletion; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000378:metabolism; D010870:Pineal Gland / Q000473:pathology; D016133:Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D000099214:Retinol-Binding Proteins, Interstitial
D005136:Eye Proteins; D019426:Integrases; D016160:Retinoblastoma Protein; D012177:Retinol-Binding Proteins; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C045073:Cre recombinase