title: Penetrance of eye defects in mice heterozygous for mutation of Gli3 is enhanced by heterozygous mutation of Pax6.
abstract: BACKGROUND
  Knowledge of the consequences of heterozygous mutations of developmentally important genes is important for understanding human genetic disorders. The Gli3 gene encodes a zinc finger transcription factor and homozygous loss-of-function mutations of Gli3 are lethal. Humans heterozygous for mutations in this gene suffer Greig cephalopolysyndactyly or Pallister-Hall syndromes, in which limb defects are prominent, and mice heterozygous for similar mutations have extra digits. Here we examined whether eye development, which is abnormal in mice lacking functional Gli3, is defective in Gli3+/- mice.
  
  
  RESULTS
  We showed that Gli3 is expressed in the developing eye but that Gli3+/- mice have only very subtle eye defects. We then generated mice compound heterozygous for mutations in both Gli3 and Pax6, which encodes another developmentally important transcription factor known to be crucial for eye development. Pax6+/-; Gli3+/- eyes were compared to the eyes of wild-type, Pax6+/- or Gli3+/- siblings. They exhibited a range of abnormalities of the retina, iris, lens and cornea that was more extensive than in single Gli3+/- or Pax6+/- mutants or than would be predicted by addition of their phenotypes.
  
  
  CONCLUSIONS
  These findings indicate that heterozygous mutations of Gli3 can impact on eye development. The importance of a normal Gli3 gene dosage becomes greater in the absence of a normal Pax6 gene dosage, suggesting that the two genes co-operate during eye morphogenesis.
authors.affiliation: Genes and Development Group, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. paulettezaki@hotmail.com
authors.forename: Paulette A
authors.initials: PA
authors.lastname: Zaki
authors.forename: J Martin
authors.initials: JM
authors.lastname: Collinson
authors.forename: Junko
authors.initials: J
authors.lastname: Toraiwa
authors.forename: T Ian
authors.initials: TI
authors.lastname: Simpson
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: Jane C
authors.initials: JC
authors.lastname: Quinn
mesh_terms: D000818:Animals; D003315:Cornea / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D005123:Eye / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D012160:Retina / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D000074290:Zinc Finger Protein Gli3
chemical_list: D005136:Eye Proteins; C465571:Gli3 protein, mouse; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D000074290:Zinc Finger Protein Gli3