Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification

• Taisuke Hosaka

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• William H. Biggs

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• David Tieu

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• Antonia D. Boyer

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• Nissi M. Varki

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• Webster K. Cavenee

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

• Karen C. Arden

  Ludwig Institute for Cancer Research, Department of Medicine, Cancer Center, and Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0660

抄録

Genetic analysis in Caenorhabditis elegans has uncovered essential roles for DAF-16 in longevity, metabolism, and reproduction. The mammalian orthologs of DAF-16, the closely-related FOXO subclass of forkhead transcription factors (FKHR/FOXO1, FKHRL1/FOXO3a, and AFX/FOXO4), also have important roles in cell cycle arrest, apoptosis and stress responses in vitro , but their in vivo physiological roles are largely unknown. To elucidate their role in normal development and physiology, we disrupted each of the Foxo genes in mice. Foxo1 -null embryos died on embryonic day 10.5 as a consequence of incomplete vascular development. Foxo1 -null embryonic and yolk sac vessels were not well developed at embryonic day 9.5, and Foxo1 expression was found in a variety of embryonic vessels, suggesting a crucial role of this transcription factor in vascular formation. On the other hand, both Foxo3a - and Foxo4 -null mice were viable and grossly indistinguishable from their littermate controls, indicating dispensability of these two members of the Foxo transcription factor family for normal vascular development. Foxo3a -null females showed age-dependent infertility and had abnormal ovarian follicular development. In contrast, histological analyses of Foxo4 -null mice did not identify any consistent abnormalities. These results demonstrate that the physiological roles of Foxo genes are functionally diverse in mammals.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 101 (9), 2975-2980, 2004-02-20

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361137045864144768
• NII論文ID: 80016527162
• DOI: 10.1073/pnas.0400093101
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0400093101
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