Canonical Wnt/β-catenin signaling is required for maintenance but not activation of Pitx2 expression in neural crest during eye development.
Pitx2 is a paired-like homeodomain gene that acts as a key regulator of eye development. Despite its significance, upstream regulation of Pitx2 expression during eye development remains incompletely understood. We use neural crest-specific ablation of Ctnnb1 to demonstrate that canonical Wnt signaling is not required for initial activation of Pitx2 in neural crest. However, canonical Wnt signaling is subsequently required to maintain Pitx2 expression in the neural crest. Eye development in Ctnnb1-null mice appears grossly normal early but significant phenotypes emerge following loss of Pitx2 expression. LEF-1 and β-catenin bind Pitx2 promoter sequences in ocular neural crest, indicating a likely direct effect of canonical Wnt signaling on Pitx2 expression. Combining our data with previous reports, we propose a model wherein a sequential code of retinoic acid followed by canonical Wnt signaling are required for activation and maintenance of Pitx2 expression, respectively. Other key transcription factors in the neural crest, including Foxc1, do not require intact canonical Wnt signaling.
Departments of Ophthalmology and Visual Sciences, and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
Amanda L
AL
Zacharias
Philip J
PJ
Gage
D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2; C497574:Lef1 protein, mouse