International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 121 - CHARACTERIZATION OF ALIEN, AN ENU-DERIVED MUTANT MOUSE WITH DEFECTS IN THE SONIC HEDGEHOG SIGNALING PATHWAY

Tran P
Genetics Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA

Co-Authors: Herron B, Parker K, Qiu H, Beier DR
Institutions: Genetics Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA

In an ENU mutagenesis screen for late embryonic developmental phenotypes caused by autosomal recessive mutations, a mutant mouse we call alien (aln) was identified that displays preaxial polydactyly, split and fused ribs, cortical layering abnormalities, and occasionally neural tube defects. This phenotype is remarkably similar to that of open brain (opb), which is caused by mutations in Rab23, a negative regulator of Shh signaling. While our mapping analysis has excluded the possibility that aln is an allele of opb, several data still place aln in the Shh pathway. The invariable presence of preaxial polydactyly suggests there is increased Shh signaling in the zone of polarizing activity of developing limb buds. Additionally, immunofluorescence with antibodies to Hnf3β, Nkx2.2 and Pax6, genes regulated by Shh signaling, show altered expression patterns in E10.5 spinal cords. Most importantly, aln/Shh double mutants have polydactylous limbs and a partial head, suggesting that the aln gene product is a negative regulator of a process that occurs downstream of Shh signaling. We have localized the mutation to chromosome 2 and are using candidate gene sequencing and mRNA analyses to positionally clone the aln gene. We are also analyzing aln/smoothened double mutants to better place our gene within the Shh pathway. Characterization of the aln mutant will further our understanding of the complex molecular network that underlies Shh signal transduction.


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