International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G20. Viable Mice Lacking M6P/IGF2 Receptor: Genome-wide Scan for Rescue from Perinatal Lethality

Jiri Forejt, Sona Gregorova, Petr Divina, Tomas Vacik, Marta Landikova and Gary Churchill*.
Institute of Molecular Genetics, AS CR, Videnska 1083, 142 20 Prague 4, Czech Republic and
*The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609 USA

The mannose 6/phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) binds M6P-bearing glycoproteins and IGF2 and transport them to lysosomes for degradation. It also activates TGF- beta and binds retinoic acid. The receptor is coded by the imprinted, maternally expressed Igf2r gene. In humans the IGF2R gene functions as a putative tumour suppressor gene in breast cancer, hepatocarcinomas and other tumours. In the mouse, the natural deletions of the gene (Thp or tLub2) or the gene knock outs have no apparent deleterious phenotype when transmitted through the male. However, when maternally derived, they act as prenatal or perinatal lethals.

Previously, we have been able to show that the lethal effect of a maternally derived Thp deletion can be rescued in inter-species hybrids of Thp females and PWD/Ph (Mus.m.musculus) males. Here we show that the genes from a PWD male parent can also rescue maternally derived tLub deletion and Igf2r- KO. By analysing the F2 generation from (Igf2r- x PWD) x (Igf2r- x PWD) intercross we could recover Igf2r-/ Igf2r- viable homozygotes, albeit at much lower than expected frequency. The phenotype of the viable mice lacking M6P/IGF2 receptor is being analysed, including the behaviour tests.

To identify the mode of inheritance of the suppression of the Tme lethality, we set up a genome-wide scan using 221 (C3H x PWD) x C3H backcross males. Each N2 male was progeny tested by crossing to +/Thp females and the frequencies of viable Thp /+ offspring were used as a quantitative trait in a QTL type of analysis. The progeny test yielded over 10 000 offspring and was completed by 199 N2 males. Only one Modifier of Tme viability (preliminary symbol - Motv1) with a major effect was identified and mapped on Chr 3. Four additional Motv loci with significant LOD scores were mapped to Chrs 2, 11, 16 and 17. An epistatic interaction between individual loci and the first analysis of possible candidate genes will be discussed.

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