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Rb is critical in a mammalian tissue stem cell population

¹ Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA; ² Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA; ³ Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; ⁴ Biomedical Informatics, Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA; ⁵ Department of Computer Science and Engineering, The Ohio State University, Columbus, Ohio 43210, USA; ⁶ Department of Biochemistry and 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 Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA

The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5). Here we show that the specific loss of Rb in trophoblast stem (TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb^–/– embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.

[Keywords: Rb; development; placenta; stem cells]

Received August 22, 2006; revised version accepted November 10, 2006.

¹⁰ Present addresses:

Department of Pathobiology, Faculty of Veterinary Medicine, University Utrecht, Utrecht 3584 CL, The Netherlands

¹¹ Zoology Department, Miami University, Oxford, Ohio 45056, USA.

¹² Corresponding authors.

E-MAIL Gustavo.Leone{at}osumc.edu; FAX (614) 292-3312.

¹³ E-MAIL Robinsm5{at}muohio.edu; FAX (513) 529-6900.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1485307

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