title: A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects.
abstract: BACKGROUND
  Genes responsible for reduced pigmentation phenotypes in rodents are associated with human developmental defects, such as Waardenburg syndrome, where patients display congenital deafness along with various abnormalities mostly related to neural crest development deficiency.
  
  
  OBJECTIVE
  In this study, we identified a spontaneous mutant mouse line Rwa, which displays variable white spots on mouse bellies and white digits and tail, on a C57BL/6N genetic background. Curly tail and spina bifida were also observed, although at a lower penetrance. These phenotypes were dominantly inherited by offspring. We searched for the genetic mechanism of the observed phenotypes.
  
  
  METHODS
  We harnessed a rapid mouse gene mapping system newly developed in our laboratories to identify a responsible gene.
  
  
  RESULTS
  We detected a region within chromosome 1 as a probable locus for the causal mutation. Dense mapping using interval markers narrowed the locus down to a 670-kbp region, containing four genes including Pax3, a gene known to be implicated in the types I and III Waardenburg syndrome. Extensive mutation screening of Pax3 detected an 841-bp deletion, spanning the promoter region and intron 1 of the gene. The defective allele of Pax3, named Pax3Rwa, lacked the first coding exon and co-segregated perfectly with the phenotypes, confirming its causal nature. The genetic background of Rwa mice is almost identical to that of inbred C57BL/6N.
  
  
  CONCLUSIONS
  These results highlight Pax3Rwamice as a beneficial tool for analyzing biological processes involving Pax3, in particular the development and migration of neural crest cells and melanocytes.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan. Electronic address: tohnishi@brain.riken.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Miura
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ohba
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Shimamoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000209:etiology / Q000235:genetics*; D000072041:PAX3 Transcription Factor / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000209:etiology / Q000235:genetics*
chemical_list: D000072041:PAX3 Transcription Factor; C068686:Pax3 protein, mouse
keywords: Belly spot; Curly tail; Linkage analysis; Melanocyte; Neural crest