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
| Autor: | Jun R. Huang, Jasmine C. Wong, Manuel Buchwald, M. Stephen Meyn, Noa Alon, Colin McKerlie |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Population Biology medicine.disease_cause Microphthalmia Mice Reproductive senescence Fanconi anemia hemic and lymphatic diseases FANCD2 Genetics medicine Animals Microphthalmos education Molecular Biology Infertility Male Genetics (clinical) Mice Knockout Mutation education.field_of_study Fetal Growth Retardation Fanconi Anemia Complementation Group A Protein Proteins nutritional and metabolic diseases Gene targeting Exons General Medicine medicine.disease Molecular biology FANCA DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Meiosis Fanconi Anemia Germ Cells Phenotype Animals Newborn Gene Targeting Female Infertility Female |
| Zdroj: | Human Molecular Genetics. 12:2063-2076 |
| ISSN: | 1460-2083 |
| Popis: | 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 Fanca(tm1Hsc) mice in which Fanca exons 1-6 were replaced by a beta-galactosidase reporter construct. Fanca(tm1.1Hsc) mice were generated by Cre-mediated removal of the neomycin cassette in Fanca(tm1Hsc) mice. Fanca(tm1.1Hsc) 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 Fanca(tm1.1Hsc) 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. Fanca(tm1Hsc) 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 Fanca(tm1Hsc) 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. |
| Databáze: | OpenAIRE |
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