title: Activation of the hedgehog signaling pathway in the developing lens stimulates ectopic FoxE3 expression and disruption in fiber cell differentiation.
abstract: OBJECTIVE
  The signaling pathways and transcriptional effectors responsible for directing mammalian lens development provide key regulatory molecules that can inform our understanding of human eye defects. The hedgehog genes encode extracellular signaling proteins responsible for patterning and tissue formation during embryogenesis. Signal transduction of this pathway is mediated through activation of the transmembrane proteins smoothened and patched, stimulating downstream signaling resulting in the activation or repression of hedgehog target genes. Hedgehog signaling is implicated in eye development, and defects in hedgehog signaling components have been shown to result in defects of the retina, iris, and lens.
  
  
  METHODS
  We assessed the consequences of constitutive hedgehog signaling in the developing mouse lens using Cre-LoxP technology to express the conditional M2 smoothened allele in the embryonic head and lens ectoderm.
  
  
  RESULTS
  Although initial lens development appeared normal, morphological defects were apparent by E12.5 and became more significant at later stages of embryogenesis. Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development. Later, inappropriate expression of the epithelial marker Pax6, and as well as fiber cell markers c-maf and Prox1 also occurred, indicating a failure of appropriate lens fiber cell differentiation accompanied by altered lens cell proliferation and cell death.
  
  
  CONCLUSIONS
  Our findings demonstrate that the ectopic activation of downstream effectors of the hedgehog signaling pathway in the mouse lens disrupts normal fiber cell differentiation by a mechanism consistent with a sustained epithelial cellular developmental program driven by FoxE3.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Kerr
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
authors.forename: Judith A
authors.initials: JA
authors.lastname: West-Mays
mesh_terms: D000483:Alleles; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics*; D004475:Ectoderm / Q000196:embryology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D020287:In Situ Nick-End Labeling; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D038081:Organogenesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D051257:Proto-Oncogene Proteins c-maf / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D005136:Eye Proteins; D051858:Forkhead Transcription Factors; C498612:Foxe3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D004247:DNA