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Extra-embryonic function of Rb is essential for embryonic development and viability

Abstract

The retinoblastoma (Rb) gene was the first tumour suppressor identified1. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2–4). However, the actual cause of the embryonic lethality has not been fully investigated. Here we show that loss of Rb leads to excessive proliferation of trophoblast cells and a severe disruption of the normal labyrinth architecture in the placenta. This is accompanied by a decrease in vascularization and a reduction in placental transport function. We used two complementary techniques—tetraploid aggregation and conditional knockout strategies—to demonstrate that Rb-deficient embryos supplied with a wild-type placenta can be carried to term, but die soon after birth. Most of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-null animals were virtually absent in rescued Rb-null pups. These findings identify and define a key function of Rb in extra-embryonic cell lineages that is required for embryonic development and viability, and provide a mechanism for the cell autonomous versus non-cell autonomous roles of Rb in development.

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Figure 1: Rb-/- mice show placental dysplasia in the labyrinth layer.
Figure 2: Loss of Rb results in higher levels of proliferation in the trophoblast cells.
Figure 3: Normal placentae and Rb-deficient fetuses reconstituted by either tetraploid aggregation or conditional knockout approaches.
Figure 4: A wild-type placenta suppresses neurogenic and erythropoietic defects of Rb-deficient animals.

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Acknowledgements

We thank A. Berns, P. Soriano and T. Jacks for providing Rb+/loxP, Mox2+/cre and Rb+/- mice, respectively. We also thank S. Hoshaw-Woodard and R. J. Jandacek for technical assistance, and C. Timmers for critical scientific discussions. This work was supported by grants from the National Cancer Institute (to G.L and T.J.R.), the National Institute of Health (to M.W. and G.L.), the National Center for Research Resources (to T.J.R.), and by the Canadian Institutes of Health Research (to J.C.C.). L.W., H.S. and A.T. were supported by NIH awards, A.d.B. was supported by a UOR Human Cancer Genetics Postdoctoral Fellowship, and G.L. is a V-Foundation and PEW Scholar.

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Correspondence to Gustavo Leone.

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Wu, L., de Bruin, A., Saavedra, H. et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947 (2003). https://doi.org/10.1038/nature01417

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