title: Truncated forms of Pax-6 disrupt lens morphology in transgenic mice.
abstract: OBJECTIVE
  Extensive literature shows that Pax-6 is critical for lens development and that Paxb mutations can result in aniridia in humans. In addition, it has been reported that truncated Pax-6 molecules can act as dominant-negative repressors of wild-type Pax-6 activity in cultured cells. This study was designed to determine whether Pax-6 molecules without either the activation domain (AD) or the homeodomain (HD) and the AD can function as dominant-negative repressors in vivo and alter the phenotype of the lens.
  
  
  METHODS
  Transgenic mice were created harboring the alphaA-crystallin promoter linked to a cDNA encoding either a truncated Pax-6 without the C terminus (paired domain [PD] + homeodomain) or Pax-6 consisting of only the PD. The phenotype of the resultant animals was investigated by light and electron microscopy as well as atomic absorption spectroscopy.
  
  
  RESULTS
  Two lines of PD + HD mice and three lines of PD mice were generated, all of which exhibit posterior nuclear and/or cortical cataracts of variable severity. The lenses from mice transgenic for either Pax-6 truncation are smaller and more hydrated than normal. Morphologically, the mice expressing the PD + HD of Pax-6 have swollen lens fibers with attenuated ball-and-socket junctions. In contrast, the lenses from mice overexpressing the PD of Pax-6 have posterior nuclear cataracts composed of cell debris, whereas the remaining fiber cells appear generally normal.
  
  
  CONCLUSIONS
  The presence of truncated Pax-6 protein in the lens is sufficient to induce cataract in a wild-type genetic background. The simplest explanation for this phenomenon is a dominant-negative effect; however, a number of other possible mechanisms are presented.
authors.affiliation: The Department of Biological Sciences, The University of Delaware, Newark 19716, USA. duncanm@udel.edu
authors.forename: M K
authors.initials: MK
authors.lastname: Duncan
authors.forename: A
authors.initials: A
authors.lastname: Cvekl
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Piatigorsky
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003459:Crystallins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005136:Eye Proteins; D019084:Fluorescent Antibody Technique, Indirect; D018398:Homeodomain Proteins / Q000235:genetics; D007908:Lens, Crystalline / Q000378:metabolism / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D008855:Microscopy, Electron, Scanning; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D011817:Rabbits; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013054:Spectrophotometry, Atomic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D003459:Crystallins; 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; D014157:Transcription Factors; D002118:Calcium