International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E11 Genetic Modifiers of a Double-Stranded (ds) RNA Binding Protein Encoding Locus (Tarbp2) that Suppress Perinatal Lethality

Bill Buaas, Antoine H. F. M. Peters, Jun Zhong and Robert E. Braun. Department of Genetics, University of Washington, Seattle, WA

The double-stranded (ds) RNA binding protein PRBP (encoded by the Tarbp2 gene) and the human orthologue (TRBP) have been implicated in gene regulation affecting germ cell development, viral responses and cellular growth. PRBP is expressed at low levels in all mouse tissues surveyed except for the testes which express this gene at high levels. PRBP encodes ~44kDA protein with three dsRNA binding domains but no other obvious sequence motifs. PRBP/TRBP has been suggested to function as a RNA chaperone for translationally regulated genes as well as a regulator of eIF2-a kinases which affect the translational initiation of mRNAs. A null mutation was generated at the Tarbp2 locus in mouse embryonic stem cells to study its in vivo requirement (J.Z., manuscript submitted). On a mixed C57BL/6Jx129/Sv background, Tarbp2-/- mice are born but exhibit growth retardation and perinatal lethality, usually at the time of weaning. However, the perinatal lethality of some mutants could be rescued at the time of weaning with dietary supplement which allowed them to live 6-10 months. We have pursued the analysis of this mutant on different genetic backgrounds to assess the role of extragenic modifiers in the above phenotypes and determine the feasibility of identifying this locus or loci.

A coisogenic 129-Tarbp2+/- strain was generated to study the mutation on this pure genetic background. 129-Tarbp2-/- mutants are born at mendelian frequencies, exhibit a growth retardation and die between 3-5 weeks. On a C57BL/6J background, Tarbp2-/- mutants are never detected at 2 weeks of age. However, analysis of e17.5 fetal litters indicates that ~50% of the expected number of mutants are present and indistinguishable from their littermates upon gross examination. These data suggest the 129 strain provides a modifier allele(s) that suppresses the early perinatal lethality. We are testing this hypothesis by generating F1 hybrid Tarbp2 mutants as well as a backcross (F1B6129 X B6) panel of animals for use in a genome-wide microsattelite marker scan. The genetic modifier(s) could provide insight into the molecular and genetic pathways PRBP is playing in somatic cells.

 


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