|Title||The patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract|
|Publication Type||Articolo su Rivista peer-reviewed|
|Year of Publication||2015|
|Authors||De Stefano, Ilaria, Tanno Barbara, Giardullo Paola, Leonardi Simona, Pasquali Emanuela, Antonelli Francesca, Tanori Mirella, Casciati Arianna, Pazzaglia Simonetta, Saran Anna, and Mancuso Mariateresa|
|Journal||American Journal of Pathology|
|Keywords||allele, Alleles, animal, animal cell, animal experiment, animal model, Animals, article, cataract, cell proliferation, Cell Surface, cell surface receptor, controlled study, Crystalline, disease predisposition, embryo development, epithelial mesenchymal transition, Epithelial-Mesenchymal Transition, epithelium cell, Female, Gene expression, gene expression profiling, gene expression regulation, genetics, genotype, Hedgehog Proteins, heterozygote, homeodomain protein, Homeodomain Proteins, immunoreactivity, Ionizing radiation, kruppel like factor, Kruppel-Like Transcription Factors, lens, lens epithelium, male, metabolism, Mice, mouse, nerve cell adhesion molecule, nonhuman, patched receptors, Pathology, pluripotent stem cell, Protein, protein expression, protein Patched 1, protein vim, radiation cataract, Radiation exposure, radiation response, Receptors, Shh protein, signal transduction, Smad protein, Smad Proteins, sonic hedgehog protein, transcription factor NANOG, transcription factor PAX6, transcription factor ZEB1, transforming growth factor beta, Transgenic, transgenic mouse, tumor suppressor gene, unclassified drug, upregulation, uvomorulin, vimentin, X ray, X-Rays, ZEB1 protein|
Age-related cataract is the most common cause of visual impairment. Moreover, traumatic cataracts form after injury to the eye, including radiation damage. We report herein that sonic hedgehog (Shh) signaling plays a key role in cataract development and in normal lens response to radiation injury. Mice heterozygous for Patched 1 (Ptch1), the Shh receptor and negative regulator of the pathway, develop spontaneous cataract and are highly susceptible to cataract induction by exposure to ionizing radiation in early postnatal age, when lens epithelial cells undergo rapid expansion in the lens epithelium. Neonatally irradiated and control Ptch1+/- mice were compared for markers of progenitors, Shh pathway activation, and epithelial-to-mesenchymal transition (EMT). Molecular analyses showed increased expression of the EMT-related transforming growth factor β/Smad signaling pathway in the neonatally irradiated lens, and up-regulation of mesenchymal markers Zeb1 and Vim. We further show a link between proliferation and the stemness property of lens epithelial cells, controlled by Shh. Our results suggest that Shh and transforming growth factor β signaling cooperate to promote Ptch1-associated cataract development by activating EMT, and that the Nanog marker of pluripotent cells may act as the primary transcription factor on which both signaling pathways converge after damage. These findings highlight a novel function of Shh signaling unrelated to cancer and provide a new animal model to investigate the molecular pathogenesis of cataract formation. © 2015 American Society for Investigative Pathology Published by Elsevier Inc. All rights reserved.
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