title: A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice.
abstract: An N-ethyl-N-nitrosourea random mutation screen was used to identify recessive modifiers of gene silencing in the mouse using an epigenetically sensitive reporter transgene. One of the mutant lines, MommeR1, was identified as a suppressor of variegation and it showed female-specific age-associated infertility in homozygotes. Linkage analysis identified a region on chromosome 10, containing the Foxo3a gene, previously shown to play a critical role in female gametogenesis. Foxo3a is a transcription factor with roles in cell cycle control, apoptosis, neural and hematopoietic cell differentiation, and DNA repair. Sequencing of the Foxo3a gene in MommeR1 mice revealed a point mutation that causes an amino acid substitution in the highly conserved Forkhead DNA-binding domain. In vitro transcription assays showed that the point mutation causes loss of FOXO3a transactivation activity. Compound heterozygotes made with Foxo3a-null mice (carrying the targeted deletion of exon 2) displayed complementation with respect to both the activation of the reporter transgene and defects in folliculogenesis similar to those seen in MommeR1 homozygotes, supporting the conclusion that this is the causative mutation. Approximately one in six female MommeR1 homozygotes develop teratomas, a phenotype not reported in Foxo3a-null mice. Ovulated oocytes from MommeR1 homozygotes display a number of abnormalities. The MommeR1 mice provide a novel platform to investigate teratocarcinogenesis and link Foxo3a with parthenogenesis and ovarian cancer. The finding of Foxo3a as a modifier of epigenetic reprogramming is discussed.
authors.affiliation: Queensland Institute of Medical Research, Herston, Brisbane, QLD, 4006, Australia.
authors.forename: N A
authors.initials: NA
authors.lastname: Youngson
authors.forename: N
authors.initials: N
authors.lastname: Vickaryous
authors.forename: A
authors.initials: A
authors.lastname: van der Horst
authors.forename: T
authors.initials: T
authors.lastname: Epp
authors.forename: S
authors.initials: S
authors.lastname: Harten
authors.forename: J S
authors.initials: JS
authors.lastname: Fleming
authors.forename: K K
authors.initials: KK
authors.lastname: Khanna
authors.forename: D M
authors.initials: DM
authors.lastname: de Kretser
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D013724:Teratoma / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse