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Nature 421, 942-947 (27 February 2003) | doi:10.1038/nature01417; Received 17 October 2002; Accepted 7 January 2003

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

Lizhao Wu1, Alain de Bruin1, Harold I. Saavedra1, Maja Starovic2, Anthony Trimboli1, Ying Yang3, Jana Opavska1, Pamela Wilson1,4, John C. Thompson4, Michael C. Ostrowski4,5, Thomas J. Rosol5,6, Laura A. Woollett7, Michael Weinstein4,5, James C. Cross2, Michael L. Robinson3,5,8 & Gustavo Leone1,4,5

  1. Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA
  2. Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA
  3. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
  4. Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA
  5. Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA
  6. Department of Biochemistry & Molecular Biology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada
  7. Division of Molecular and Human Genetics, Children's Research Institute, Columbus, Ohio 43205, USA
  8. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA

Correspondence to: Gustavo Leone1,4,5 Correspondence and requests for materials should be addressed to G.L. (e-mail: Email: Leone-1@medctr.osu.edu).

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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.

  1. Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA
  2. Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA
  3. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
  4. Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA
  5. Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA
  6. Department of Biochemistry & Molecular Biology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada
  7. Division of Molecular and Human Genetics, Children's Research Institute, Columbus, Ohio 43205, USA
  8. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA

Correspondence to: Gustavo Leone1,4,5 Correspondence and requests for materials should be addressed to G.L. (e-mail: Email: Leone-1@medctr.osu.edu).