title: Pitx3 directly regulates Foxe3 during early lens development.
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 Parkinsons 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.
authors.affiliation: Helmholtz Center Munich, Institute of Developmental Genetics, Neuherberg, Germany.
authors.forename: Nafees
authors.initials: N
authors.lastname: Ahmad
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: Doris
authors.initials: D
authors.lastname: Muenster
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Khan
authors.forename: Peter
authors.initials: P
authors.lastname: Carlsson
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
mesh_terms: D000818:Animals; D001035:Aphakia / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D007908:Lens, Crystalline / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014404:Tubulin / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D038222:gamma-Crystallins / Q000096:biosynthesis; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498612:Foxe3 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D014404:Tubulin; D025521:Tumor Suppressor Proteins; D038222:gamma-Crystallins; C433629:homeobox protein PITX3; D000098551:Prospero-Related Homeobox 1 Protein