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Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 2063-2076
DOI: 10.1093/hmg/ddg219
© 2003 Oxford University Press

Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia

Jasmine C.Y. Wong1,2,*, Noa Alon1, Colin Mckerlie3,5, Jun R. Huang1, M. Stephen Meyn1,2,4 and Manuel Buchwald1,2

1Program in Genetics and Genomics Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, 2Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada, 3Integrative Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, 4Department of Pediatrics, and 5Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Received May 6, 2003; Revised June 12, 2003; Accepted June 23, 2003

Fanconi Anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents. Recent studies suggest that FA proteins share a common pathway with BRCA proteins. To study the in vivo role of the FA group A gene (Fanca), gene-targeting techniques were used to generate Fancatm1Hsc mice in which Fanca exons 1–6 were replaced by a ß-galactosidase reporter construct. Fancatm1.1Hsc mice were generated by Cre-mediated removal of the neomycin cassette in Fancatm1Hsc mice. Fancatm1.1Hsc homozygotes display FA-like phenotypes including growth retardation, microphthalmia and craniofacial malformations that are not found in other Fanca mouse models, and the genetic background affects manifestation of certain phenotypes. Both male and female mice homozygous for Fanca mutation exhibit hypogonadism, and homozygous females demonstrate premature reproductive senescence and an increased incidence of ovarian cysts. We showed that fertility defects in Fancatm1.1Hsc homozygotes might be related to a diminished population of primordial germ cells (PGCs) during migration into the gonadal ridges. We also found a high level of Fanca expression in pachytene spermatocytes. Fancatm1Hsc homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. However, the localization of Rad51, Brca1, Fancd2 and Mlh1 appeared normal on Fancatm1Hsc homozygous meiotic chromosomes. Taken together, our results suggest that the FA pathway plays a role in the maintenance of reproductive germ cells and in meiotic recombination.

* To whom correspondence should be addressed. Tel: +1 4168136361; Fax: +1 4168134931; Email: jcywong{at}sickkids.ca


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