Homeodomain protein Pitx3 maintains the mitotic activity of lens epithelial cells.
Pitx3 is a bicoid like homeobox transcription factor of which deficiency in mice is linked with the aphakia phenotype. Mutation in human PITX3 gene is associated with autosomal dominant cataract with variable anterior segment mesenchymal dysgenesis. However, the molecular events causing the morphological changes in aphakia remains unknown. In this study we investigated the behaviour of GFP tagged Pitx3 null embryonic stem cells in chimeric lens, as well as the molecular features of the Pitx3-deficient lens of homozygous Pitx3 knockout mice. We show that the lack of colonisation of Pitx3-deficient ES cell derivatives in Pitx3 wild-type<-->Pitx3 null chimeric lens was due to the depletion of the epithelial cells in lens epithelium manifested by aberrant cell cycle exit and precocious onset of fibre cell differentiation of the Pitx3 null cells at the lens vesicle stage. This was demonstrated by the early activation of the cell cycle inhibitors p27Kip1 and p57Kip2, and the expression of beta-and gamma-crystallins. These defects are at least partially attributed to the loss of FoxE3 and misexpression of Prox1 in the lens vesicle epithelial cells. Thus, Pitx3 is essential to maintain lens epithelial phenotype and prevent inappropriate fibre cell differentiation during lens development.
Ho
Hsin-Yi
HY
Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UK.
Chang
Kuo-Hsuan
KH
Nichols
Jennifer
J
Li
Meng
M
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007908:Lens, Crystalline / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D038204:beta-Crystallins / Q000378:metabolism; D038222:gamma-Crystallins / Q000378:metabolism
D015820:Cadherins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D038204:beta-Crystallins; D038222:gamma-Crystallins; C433629:homeobox protein PITX3; D020796:Receptor, Platelet-Derived Growth Factor alpha