Truncated forms of Pax-6 disrupt lens morphology in transgenic mice.

Abstract

PURPOSE:

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: M K Duncan, A Cvekl, X Li, J Piatigorsky
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 41 Issue 2 Pg. 464-73 (Feb 2000) ISSN: 0146-0404 [Print] United States
• PMID: 10670477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Crystallins
• DNA-Binding Proteins
• Eye Proteins
• Homeodomain Proteins
• PAX6 Transcription Factor
• PAX6 protein, human
• Paired Box Transcription Factors
• Pax6 protein, mouse
• Repressor Proteins
• Transcription Factors
• Calcium

Topics

• Animals
• CHO Cells
• Calcium (metabolism)
• Cataract (genetics, metabolism, pathology)
• Cricetinae
• Crystallins (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Eye Proteins
• Fluorescent Antibody Technique, Indirect
• Homeodomain Proteins (genetics)
• Lens, Crystalline (metabolism, ultrastructure)
• Mice
• Mice, Transgenic (genetics)
• Microscopy, Electron, Scanning
• PAX6 Transcription Factor
• Paired Box Transcription Factors
• Phenotype
• Rabbits
• Repressor Proteins (genetics, metabolism)
• Spectrophotometry, Atomic
• Transcription Factors (genetics, metabolism)
• Transfection