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David Cobrinik, Xiaoliang L. Xu, Suresh C. Jhanwar, David H. Abramson; Transgenic Mice with a Humanized Pattern of MDM2 Expression for Retinoblastoma Modeling. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2478.
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© ARVO (1962-2015); The Authors (2016-present)
Retinoblastomas form in response to RB1 mutations in the developing human retina. Of interest, the tumors appear to occur uniquely in humans, implying that developmental features that are specific to the human retina have a crucial role in retinoblastoma tumorigenesis. To evaluate the human retinal features that underlie this phenomenon, we examined the cellular and molecular properties of human retinoblastoma samples. Our studies showed that retinoblastomas have properties of cone precursor tumors and depend upon cone-specific signaling circuitry (Xu et al., 2009, Cell 137:1018). In particular, retinoblastoma cells were found to require the cone-specific transcription factors RXRgamma and TRbeta 2, which are generally prominent in mammalian cones, and required MDM2 and N-Myc, which were prominent in human but not mouse cones. These findings raise the possibility that the human-specific pattern of MDM2 and/or N-Myc expression sensitizes cone precursors to the oncogenic effects of RB1 inactivation. To evaluate this possibility, we aim to determine whether ectopic expression of MDM2 and/or N-Myc sensitizes mouse cone precursors to the inactivation of Rb1. As a first step towards this goal, we constructed transgenic mice with prominent cone precursor-specific MDM2 expression.
An RGP-MDM2 transgene was produced, consisting of the Red-Green Opsin Promoter driving full-length human MDM2 cDNA and additional regulatory elements. The transgene was introduced into mice in a pure C57Bl/6 background. Retinal MDM2 expression was evaluated by immunohistochemical staining.
Ten founder mice carrying the RGP-MDM2 transgenic lines were produced, of which six propagated the transgene in the germline and displayed cone- and cone precursor-specific human MDM2 expression. None of the transgenic lines displayed human MDM2 in cells other than cones.
We produced transgenic mice with cone-specific MDM2 expression mimicking that of the human retina. These mice may now be bred with others that have retina- and/or cone-specific Rb1 inactivation, to assess whether cone-specific MDM2 expression underlies the uniquely human susceptibility to retinoblastoma tumorigenesis.
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