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Pitx3 directly regulates Foxe3 during early lens development.

Journal article
Authors Nafees Ahmad
Muhammad Aslam
Doris Muenster
Marion Horsch
Muhammad A Khan
Peter Carlsson
Johannes Beckers
Jochen Graw
Published in The International journal of developmental biology
Volume 57
Pages 741-751
ISSN 1696-3547
Publication year 2013
Published at Department of Chemistry and Molecular Biology
Pages 741-751
Language en
Links dx.doi.org/10.1387/ijdb.130193jg
Subject categories Basic Medicine

Abstract

Pitx3 is a bicoid-related homeodomain transcription factor critical for the development of the ocular lens, mesencephalic dopaminergic neurons and skeletal muscle. In humans, mutations in PITX3 are responsible for cataracts and anterior segment abnormalities of varying degree; polymorphisms are associated with Parkinson’s disease. In aphakia (ak) mice, two deletions in the promoter region of Pitx3 cause abnormal lens development. Here, we investigated systematically the role of Pitx3 in lens development including its molecular targets responsible for the ak phenotype. We have shown that ak lenses exhibit reduced proliferation and aberrant fiber cell differentiation. This was associated with loss of Foxe3 expression, complete absence of Prox1 expression, reduced expression of epsilon-tubulin and earlier expression of gamma-crystallin during lens development. Using EMSA and ChIP assays, we demonstrated that Pitx3 binds to an evolutionary conserved bicoid-binding site on the 5’-upstream region of Foxe3. Finally, Pitx3 binding to 5’-upstream region of Foxe3 increased transcriptional activity significantly in a cell-based reporter assay. Identification of Foxe3 as a transcriptional target of Pitx3 explains at least in part some of the phenotypic similarities of the ak and dyl mice (dysgenic lens, a Foxe3 allele). These findings enhance our understanding of the molecular cascades which subserve lens development.

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