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Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice
A Poltorak1, I Smirnova, R Clisch
1University of Texas Southwestern Medical Center, Dallas, USA.
Abstract:
Proceeding from our observation that LPS-unresponsive mice of the strain C57BL/10ScCr mice fail to express the Tlr4 gene [Poltorak A, He X. Smirnova I et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085], we have defined the exact limits of a deletion encompassing Tlr4 in the C57BL/10ScCr genome. The deletion removes 74723 bp of DNA, with reference to the control strain 129/J (from which the complete sequence of the Tlr4 locus was obtained). There is no inserted element, and no re-arrangement of the chromosome (e.g. inversion or translocation) in the immediate region of Tlr4; the deletion removes only one recognizable gene. Hence, other immunological anomalies that have been identified in C57BL/10ScCr mice (a non-healing phenotype in Leishmania inoculation and failure to produce interferon-gamma in response to numerous microbial infections) must be ascribed to one of two causes. Mutation(s) at other loci may be responsible for these defects. Alternatively, Tlr4 locus deletion may have phenotypic consequences that exceed the well known blockade of LPS signal transduction.
Insights
Researchers identified a 74,723 bp deletion in the Toll-like receptor 4 (Tlr4) gene in C57BL/10ScCr mice. This deletion explains their LPS unresponsiveness and may cause other observed immune defects.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- C57BL/10ScCr mice exhibit lipopolysaccharide (LPS) unresponsiveness, linked to the Tlr4 gene.
- Previous studies indicated mutations in the Tlr4 gene in LPS-unresponsive mouse strains.
Purpose of the Study:
- To precisely define the genetic deletion encompassing the Tlr4 gene in C57BL/10ScCr mice.
- To investigate the genetic basis of observed immunological anomalies in these mice.
Main Methods:
- Comparative genomic analysis between C57BL/10ScCr and control 129/J mouse strains.
- DNA sequencing to identify the exact boundaries of the Tlr4 deletion.
Main Results:
- A deletion of 74,723 bp, relative to the 129/J strain, was identified in the Tlr4 locus of C57BL/10ScCr mice.
- The deletion removes only the Tlr4 gene without evidence of inserted elements or chromosomal rearrangements.
- This deletion directly explains the LPS unresponsiveness in C57BL/10ScCr mice.
Conclusions:
- The identified Tlr4 gene deletion is the cause of LPS signal transduction blockade in C57BL/10ScCr mice.
- Other immunological defects in these mice may result from this deletion's broader consequences or mutations at other loci.