title: The Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract.
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.
authors.affiliation: Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: De Stefano
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanno
authors.affiliation: Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Giardullo
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Leonardi
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasquali
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonelli
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Tanori
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy. Electronic address: anna.saran@enea.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy. Electronic address: mariateresa.mancuso@enea.it.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
mesh_terms: D000483:Alleles; D000818:Animals; D002386:Cataract / Q000378:metabolism*; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D014965:X-Rays; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014746:Vimentin; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1