Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development.
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.
Black
Graeme C M
GC
Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, UK.
Mazerolle
Chantal J
CJ
Wang
Yaping
Y
Campsall
Katrina D
KD
Petrin
Dino
D
Leonard
Brian C
BC
Damji
Karim F
KF
Evans
D Gareth
DG
McLeod
David
D
Wallace
Valerie A
VA
D000818:Animals; D001478:Basal Cell Nevus Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D012160:Retina / Q000002:abnormalities* / Q000254:growth & development / Q000648:ultrastructure; D015792:Retinal Dysplasia / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators