title: Corneal development, limbal stem cell function, and corneal epithelial cell migration in the Pax6(+/-) mouse.
abstract: OBJECTIVE
  To investigate the etiology of corneal dysfunction in the Pax6(+/-) mouse model of aniridia-related keratopathy.
  
  
  METHODS
  Mosaic patterns of X-gal staining were compared in the corneal and limbal epithelia of female Pax6(+/-) and Pax6(+/+) littermates, age 3 to 28 weeks, hemizygous for an X-linked LacZ transgene, and Pax6(+/+), LacZ(-)<-->Pax6(+/+), LacZ(+) and Pax6(+/+), LacZ(-)<-->Pax6(+/-), LacZ(+) chimeras. Histologic examination of chimeric corneas was performed.
  
  
  RESULTS
  Disrupted patterns of X-gal staining showed that heterozygosity for Pax6 perturbed clonal patterns of growth and development in the corneal and limbal epithelium. Centripetal migration of Pax6(+/-) corneal epithelial cells was diverted. Normal patterns of centripetal Pax6(+/-) cell migration and epithelial morphology were restored in Pax6(+/+)<-->Pax6(+/-) chimeras. Fewer, larger clones of limbal stem cells were present in Pax6(+/-) eyes, compared with wild-type. In the chimeras, Pax6(+/-) limbal stem cells were cell-autonomously depleted or less efficient than wild-type cells at producing progeny to populate the corneal epithelium.
  
  
  CONCLUSIONS
  The correct Pax6 dosage is necessary for normal clonal growth during corneal development, normal limbal stem cell activity, and correct corneal epithelial cell migration. Disruption of normal cell movement in heterozygotes may be the consequence of failure of nonautonomous guidance cues. Degeneration of the corneal surface in aniridia-related keratopathy relates to both a deficiency within the limbal stem cell niche and nonautonomous diversion of corneal epithelial cell migration.
authors.affiliation: Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom. m.collinson@abdn.ac.uk
authors.forename: J Martin
authors.initials: JM
authors.lastname: Collinson
authors.forename: Simon A
authors.initials: SA
authors.lastname: Chanas
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.forename: John D
authors.initials: JD
authors.lastname: West
mesh_terms: D000818:Animals; D015783:Aniridia / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D002678:Chimera; D003315:Cornea / Q000254:growth & development*; D003316:Corneal Diseases / Q000235:genetics / Q000473:pathology; D019573:Epithelium, Corneal / Q000473:pathology*; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D005697:Galactosides / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D007211:Indoles / Q000378:metabolism; D007763:Lac Operon; D016850:Limbus Corneae / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D013234:Stem Cells / Q000502:physiology*
chemical_list: D005136:Eye Proteins; D005697:Galactosides; D018398:Homeodomain Proteins; D007211:Indoles; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside