Pax6 is essential for lens fiber cell differentiation.
The developing ocular lens provides an excellent model system with which to study the intrinsic and extrinsic cues governing cell differentiation. Although the transcription factors Pax6 and Sox2 have been shown to be essential for lens induction, their later roles during lens fiber differentiation remain largely unknown. Using Cre/loxP mutagenesis, we somatically inactivated Pax6 and Sox2 in the developing mouse lens during differentiation of the secondary lens fibers and explored the regulatory interactions of these two intrinsic factors with the canonical Wnt pathway. Analysis of the Pax6-deficient lenses revealed a requirement for Pax6 in cell cycle exit and differentiation into lens fiber cells. In addition, Pax6 disruption led to apoptosis of lens epithelial cells. We show that Pax6 regulates the Wnt antagonist Sfrp2 in the lens, and that Sox2 expression is upregulated in the Pax6-deficient lenses. However, our study demonstrates that the failure of differentiation following loss of Pax6 is independent of beta-catenin signaling or Sox2 activity. This study reveals that Pax6 is pivotal for initiation of the lens fiber differentiation program in the mammalian eye.
Shaham
Ohad
O
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Smith
April N
AN
Robinson
Michael L
ML
Taketo
Makoto M
MM
Lang
Richard A
RA
Ashery-Padan
Ruth
R
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D003459:Crystallins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D007908:Lens, Crystalline / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D003459:Crystallins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C098693:Sox1 protein, mouse; C527783:Sox2 protein, mouse; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000098551:Prospero-Related Homeobox 1 Protein