The Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract.

TitleThe Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract.
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2015
AuthorsDe Stefano, Ilaria, Tanno Barbara, Giardullo Paola, Leonardi Simona, Pasquali Emanuela, Antonelli Francesca, Tanori Mirella, Casciati Arianna, Pazzaglia Simonetta, Saran Anna, and Mancuso Mariateresa
JournalAm J Pathol
Volume185
Issue1
Pagination85-95
Date Published2015 Jan
ISSN15252191
KeywordsAlleles, Animals, cataract, cell proliferation, Epithelial-Mesenchymal Transition, gene expression profiling, gene expression regulation, Hedgehog Proteins, heterozygote, Homeodomain Proteins, Kruppel-Like Transcription Factors, Lens, Crystalline, Mice, Mice, Transgenic, patched receptors, Patched-1 Receptor, Receptors, Cell Surface, signal transduction, Smad Proteins, transforming growth factor beta, vimentin, X-Rays, Zinc Finger E-box-Binding Homeobox 1
Abstract

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.

DOI10.1016/j.ajpath.2014.09.019
Alternate JournalAm. J. Pathol.
PubMed ID25452120