title: Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities.
abstract: Aniridia in man and Small eye in mice are semidominant developmental disorders caused by mutations within the paired box gene PAX6. Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes and nasal cavities and exhibit brain abnormalities. To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus. When crossed onto the Small eye background, the transgene rescues the mutant phenotype. Strikingly, mice carrying multiple copies on a wild-type background show specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Thus, at least five different eye phenotypes are associated with changes in PAX6 expression. We provide evidence that not only reduced, but also increased levels of transcriptional regulators can cause developmental defects.
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Schedl
authors.forename: A
authors.initials: A
authors.lastname: Ross
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Engelkamp
authors.forename: P
authors.initials: P
authors.lastname: Rashbass
authors.forename: V
authors.initials: V
authors.lastname: van Heyningen
authors.forename: N D
authors.initials: ND
authors.lastname: Hastie
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005136:Eye Proteins; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005816:Genetic Complementation Test; D018398:Homeodomain Proteins; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D012097:Repressor Proteins; D019076:Transgenes / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins