Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development

• Published in: Human molecular genetics 2003-12, Vol.12 (24), p.3269-3276
• Main Authors: Black, Graeme C.M., Mazerolle, Chantal J., Wang, Yaping, Campsall, Katrina D., Petrin, Dino, Leonard, Brian C., Damji, Karim F., Evans, D. Gareth, McLeod, David, Wallace, Valerie A.
• Format: Article
• Language: English
• Subjects: Animals; Basal Cell Nevus Syndrome - genetics; Basal Cell Nevus Syndrome - metabolism; Basal Cell Nevus Syndrome - pathology; Biological and medical sciences; Classical genetics, quantitative genetics, hybrids; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetics of eukaryotes. Biological and molecular evolution; Gorlin syndrome; Hedgehog protein; Hedgehog Proteins; Human; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mutation; Patched gene; Patched Receptors; Patched-1 Receptor; Receptors, Cell Surface; Retina - abnormalities; Retina - growth & development; Retina - ultrastructure; Retinal Dysplasia - genetics; Retinal Dysplasia - pathology; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddg356

Mutations in Patched (PTCH), encoding the Hedgehog (Hh) receptor, underlie Basal Cell Naevus syndrome (BCNS) and, in addition to tumor predisposition, are associated with a wide range of ‘patterning’ defects. The basis for the underlying patterning problems in Hh-dependent tissues in BCNS and their long-term consequences on tissue homeostasis are, however, not known. Hh signaling is required for normal growth and organization of the mammalian retina and we show that PtchlacZ+/− mice exhibit vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ+/− mice exhibit abnormal cell cycle regulation, which culminates in photoreceptor dysplasia and Müller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs are a cause of significant visual loss in the general, especially elderly, population. We hypothesize that alteration of Müller cell Hh signaling may play a role in the pathogenesis of such age-related ‘idiopathic’ ERMs.