Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

  1. Scott Houghtaling1,5,
  2. Cynthia Timmers1,
  3. Meenakshi Noll1,
  4. Milton J. Finegold3,
  5. Stephen N. Jones4,
  6. M. Stephen Meyn2, and
  7. Markus Grompe1
  1. 1 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97239, USA
  2. 2 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada M5S 1A8
  3. 3 Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA
  4. 4 Department of Cell Biology, University of Massachusetts Medical School, North Worcester, Massachusetts 01605, USA

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability.

Keywords

Footnotes

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

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1103403.

  • ↵5 Corresponding author. E-MAIL houghtal{at}ohsu.edu; FAX (503) 494-6886.

    • Accepted June 6, 2003.
    • Received April 14, 2003.
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  1. Published in Advance July 31, 2003, doi: 10.1101/gad.1103403 Genes & Dev. 17: 2021-2035 Cold Spring Harbor Laboratory Press

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