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

F27 Characterization of a Phenocopy of Waved Mice

Bruce Herron, Lisa Pacella, Dorothee Foernzler, Cherie VanDoren, and David Beier. Division of Genetics, Brigham and Women's Hospital; Harvard Medical School Boston, MA

We have discovered a novel recessive mutation affecting skin and hair development in mice. Mutant mice have open eyes at birth and vibrissae that are often abnormally curled. Hair growth initially appears normal; however, by two weeks of age the entire coat appears wavy.

To investigate the possibility that this mutation is a new allele of waved 1 (wa1) or waved 2 (wa2), we mapped this mutation in an intercross and have localized it to proximal mouse Chr. 7. Therefore, this mutation is not allelic with either wa1 or wa2, which map to Chr. 6 and 11 respectively, and has been designated as waved 3 (wa3).

The genes affected in wa1 and wa2 mice have been identified. Transforming growth Factor alpha (TGFa) is a widely expressed growth factor that is under-expressed inwa1/wa1 mice. A null mutation in TGFa, created by homologous recombination, has an identical phenotype to wa1. Epidermal growth factor receptor (EGFr), the receptor for TGFa, is mutated in wa2/wa2 mice. This ligand/receptor pathway has been investigated extensively; however, little is known about other genes that participate in the signaling process.

While wa3 has not been proven to participate in the TGFa signaling pathway, the phenotype is strikingly similar to wa1 andwa2. Furthermore, mutations are known to occur in genes in Drosophila (e.g.rho and Star) that have a phenotype identical to a null mutation of the Drosophila TGFa homologue spitz. These observations raise the possibility that the TGFa signaling pathway requires additional genes to function normally. We propose that the wa3 mutation is in a gene that is a member of the TGFa signal cascade. Characterization of this gene product will lead to a better understanding of the TGFa signaling pathway.

The wa3 non-recombinant interval has conserved homology with human chromosome 19q13.2. The human genomic DNA corresponding to this interval has been completely sequenced. Additionally we have isolated several mouse BAC's that encompass the wa3 interval. Together, these reagents will provide several candidates for analysis in mutant mice.

 


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