International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 23 - Homozygosity For Two N-ethyl-N-nitrosourea (ENU)-induced And A Gene-trap Mutations Of The Cytoplasmic FMRP-interacting Protein 1 (Cyfip1) Results In Embryonic Lethal Phenotype In Mice

Li L 1, Mentzer S 2, Nicholls RD 3, Carpenter D 2, Rinchik E 2, Johnson D 2, You Y 2

1Graduate School of Genome Science and Technology, University of Tennessee-Oak Ridge National Laboratory. 2 Mammalian Genetics and Genomics Group, Life Sciences Division, Oak Ridge National Laboratory. 3Department of Psychiatry, University of Pennsylvania.

The functional unit l71Rl has been defined as a peri-implantation lethal locus by complementation analysis of deficiencies in the p-region of mouse Chromosome 7.  Previous characterization of the genomic region indicated that the l71Rl interval contains 4 genes including the Cytoplasmic FMRP (Fragile-X Mental Retardation Protein)-interacting protein 1 (Cyfip1), also known as Shyc or Sra-1Cyfip1 was considered to be the most likely candidate gene among the four to cause the peri-implantation lethal phenotype.  Subsequently, a Cyfip1 gene-trap ES cell line was identified in the BayGenomics gene-trap ES cell clone library, and heterozygous Cyfip1GT/+ mice were generated from the chimeric mice derived from a Cyfip1 gene-trap ES cell clone.  However, Cyfip1GT/GT homozygotes do not show peri-implantation lethality.  Instead, the homozygous Cyfip1GT/GT embryos implant and the development appears normal until 7.5-8.5 dpc, after which the embryos manifest abnormalities and remain in lordotic position.  The mutant embryos are subsequently disintegrating after 10.5 dpc.  Previously, two N-ethyl-N-nitrosourea (ENU)-induced embryonic lethal mutations, stocks 785DSJ and 828DSJ, were mapped within the l71Rl critical interval.  We performed intra- and inter-crosses for these two ENU-induced mutations as well as allelism tests with Cyfip1GT/+ mice.  The results unambiguously indicated that these three mutations are allelic and the homozygous or compound heterozygous mutants display the same embryonic abnormalities after 8.5 dpc. Therefore, we concluded that the two ENU mutations are also Cyfip1 gene mutations and have identified the mutations at the molecular level.  Our preliminary results suggest that Cyfip1 plays an important role in mouse embryonic development.  The function of Cyfip1 in the mouse development is being analyzed by molecular and cellular approaches. 

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