Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3269-3276
DOI: 10.1093/hmg/ddg356
© 2003 Oxford University Press
Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development
1Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Hathersage Road, Manchester, UK, 2Academic Department of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester, UK, 3Centre for Molecular Medicine, Stopford Building, Oxford Road, Manchester, UK, 4Molecular Medicine Program, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada and 5University of Ottawa Eye Institute, 501 Smyth Road, Ottawa, Ontario, Canada
Received July 10, 2003; Accepted October 6, 2003
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.
* To whom correspondence should be addressed at: Ottawa Health Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Tel: +1 6137378234; Fax: +1 6137378803; Email: vwallace{at}ohri.ca
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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