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Vol. 12, No. 11, pp. 1599-1609, June 1, 1998
1 Division of Molecular Genetics and
2 Division
of Molecular Carcinogenesis, The Netherlands Cancer Institute,
Amsterdam, The Netherlands;
4 Institut National de la
Santé et de la Recherche Médicale (INSERM) U450,
Affiliée Centre National de la Recherche Scientifique (CNRS),
Paris, France
Hemizygosity for the retinoblastoma gene RB in man
strongly predisposes to retinoblastoma. In the mouse, however,
Rb hemizygosity leaves the retina normal, whereas in
Rb
/ chimeras pRb-deficient
retinoblasts undergo apoptosis. To test whether concomitant
inactivation of the Rb-related gene p107 is required to
unleash the oncogenic potential of pRb deficiency in the mouse retina,
we inactivated both Rb and p107 by homologous recombination in embryonic stem cells and generated chimeric mice. Retinoblastomas were found in five out of seven adult
pRb/p107-deficient chimeras. The retinal tumors showed
amacrine cell differentiation, and therefore originated from cells
committed to the inner but not the outer nuclear layer. Retinal lesions
were already observed at embryonic day 17.5. At this stage, the
primitive nuclear layer exhibited severe dysplasia, including
rosette-like arrangements, and apoptosis. These findings provide formal
proof for the role of loss of Rb in retinoblastoma development
in the mouse and the first in vivo evidence that p107 can exert
a tumor suppressor function.
[Key Words: Retinoblastoma; apoptosis; Rb; p107; tumor suppressor gene; chimeric mice]
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