International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

09:00 - 09:15 HRS

Lps2, A NOVEL AND CRUCIAL COMPONENT OF THE LPS SIGNALING PATHWAY, IDENTIFIED BY GERMLINE SATURATION MUTAGENESIS WITH ENU.

K Hoebe
The Scripps Research Institute

Co-Authors: Du X, Goode J, Tabeta K, Mann J, Beutler B
Institutions: The Scripps Research Institute

Tlr4 was recently identified as the product of the Lps locus by positional cloning, and serves as the core transducer of the mammalian lipopolysaccharide (LPS) receptor.  However, not all of the proteins that participate in LPS signaling have been identified. In order to find other essential components of the signaling apparatus, we have initiated an ENU mutagenesis program, involving the generation of both F1 and F3 mutants on the background strain C57BL/6. To date, more than 1500 F1 and 1900 F3 males have been screened for LPS sensing, using TNF-a production by peritoneal macrophages ex vivo as a read-out. A single, strong phenodeviant (an LPS non-responder) was identified by the screen.  The phenotype was found to be transmissible (conferred by an autosomal recessive mutation), and was penetrant on both C57BL/6 and C3H/HeN backgrounds.  The mutation is specific in its effects on LPS signaling, insofar as mice homozygous for the mutation have no defect of CpG or peptidoglycan sensing.  The locus involved was therefore designated Lps2.  The Lps2 locus has been mapped to a 3 cM interval using microsatellite markers. None of the genes that are currently known to mediate LPS sensing reside in the critical region; therefore, we believe that the Lps2 mutation involves a gene that was not previously known to be required for LPS responses.


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