Cutting edge: functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lpsn gene: in vivo evidence for a dominant negative mutation.
A point mutation in the Tlr4 gene, which encodes Toll-like receptor 4, has recently been proposed to underlie LPS hyporesponsiveness in C3H/HeJ mice (Lpsd). The data presented herein demonstrate that F1 progeny from crosses between mice that carry a approximately 9-cM deletion of chromosome 4 (including deletion of LpsTlr4) and C3H/HeJ mice (i.e., Lps0 x Lpsd F1 mice) exhibit a pattern of LPS sensitivity, measured by TNF activity, that is indistinguishable from that exhibited by Lpsn x Lpsd F1 progeny and whose average response is "intermediate" to parental responses. Thus, these data provide clear functional support for the hypothesis that the C3H/HeJ defect exerts a dominant negative effect on LPS sensitivity; however, expression of a normal Toll-like receptor 4 molecule is apparently not required.
Vogel
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SN
Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. vogel@bob.usuf2.usuhs.mil
Johnson
D
D
Perera
P Y
PY
Medvedev
A
A
Larivière
L
L
Qureshi
S T
ST
Malo
D
D
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D029721:Drosophila Proteins; D005838:Genotype; D006239:Haplotypes; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H / Q000235:genetics* / Q000276:immunology; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000235:genetics*; D017384:Sequence Deletion; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha