Jonathan Bibliowicz1, Jeffrey M Gross. 1. Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, Texas, USA.
Abstract
PURPOSE: Patched is a well-studied tumor suppressor and negative regulator of the Hedgehog (Hh) pathway. Earlier work in this laboratory has shown that embryonic zebrafish patched2 (ptc2) mutant retinas possess an expanded ciliary marginal zone (CMZ) and phenotypes similar to those in human patients with basal cell naevus syndrome (BCNS), a congenital disorder linked to mutations in the human PTCH gene. This study extends the analysis of retinal structure and homeostasis in ptc2-/- mutants to juvenile stages, to determine whether Patched 2 function is essential in the postembryonic eye. METHODS: Histologic, immunohistochemical, and molecular analyses were used to characterize retinal defects in the 6-week-old juvenile ptc2-/- retina. RESULTS: Juvenile ptc2-/- mutants exhibited peripheral retinal dysplasias that included the presence of ectopic neuronal clusters in the inner nuclear layer (INL) and regions of disrupted retinal lamination. Retinal dysplasias were locally associated with ectopic proliferation. BrdU/EdU labeling and immunohistochemistry assays demonstrated that a population of ectopically proliferating cells gave rise to the ectopic neuronal clusters in the INL of ptc2-/- mutants and that this contributed to retinal dysplasia in the mutant eye. CONCLUSIONS: These results demonstrate a direct link between overproliferation and retinal dysplasia in the ptc2-/- juvenile retina and establish ectopic proliferation as the likely cellular underpinning of retinal dysplasia in juvenile ptc2-/- mutants.
PURPOSE: Patched is a well-studied tumor suppressor and negative regulator of the Hedgehog (Hh) pathway. Earlier work in this laboratory has shown that embryonic zebrafishpatched2 (ptc2) mutant retinas possess an expanded ciliary marginal zone (CMZ) and phenotypes similar to those in humanpatients with basal cell naevus syndrome (BCNS), a congenital disorder linked to mutations in the humanPTCH gene. This study extends the analysis of retinal structure and homeostasis in ptc2-/- mutants to juvenile stages, to determine whether Patched 2 function is essential in the postembryonic eye. METHODS: Histologic, immunohistochemical, and molecular analyses were used to characterize retinal defects in the 6-week-old juvenile ptc2-/- retina. RESULTS: Juvenile ptc2-/- mutants exhibited peripheral retinal dysplasias that included the presence of ectopic neuronal clusters in the inner nuclear layer (INL) and regions of disrupted retinal lamination. Retinal dysplasias were locally associated with ectopic proliferation. BrdU/EdU labeling and immunohistochemistry assays demonstrated that a population of ectopically proliferating cells gave rise to the ectopic neuronal clusters in the INL of ptc2-/- mutants and that this contributed to retinal dysplasia in the mutant eye. CONCLUSIONS: These results demonstrate a direct link between overproliferation and retinal dysplasia in the ptc2-/- juvenile retina and establish ectopic proliferation as the likely cellular underpinning of retinal dysplasia in juvenile ptc2-/- mutants.
Authors: Ani V Das; Kavita B Mallya; Xing Zhao; Faraz Ahmad; Sumitra Bhattacharya; Wallace B Thoreson; Ganapati V Hegde; Iqbal Ahmad Journal: Dev Biol Date: 2006-07-29 Impact factor: 3.582
Authors: H Hahn; C Wicking; P G Zaphiropoulous; M R Gailani; S Shanley; A Chidambaram; I Vorechovsky; E Holmberg; A B Unden; S Gillies; K Negus; I Smyth; C Pressman; D J Leffell; B Gerrard; A M Goldstein; M Dean; R Toftgard; G Chenevix-Trench; B Wainwright; A E Bale Journal: Cell Date: 1996-06-14 Impact factor: 41.582