The hedgehog pathway in retinal development and disease

Abstract

The Hedgehog receptor Patched (Ptch) is a well-studied tumor suppressor. Mutations in Ptch have been linked to mis-regulation of stem cell proliferation and tumorigenesis in numerous contexts. To study the role of Ptch function during retinal development and homeostasis, I analyzed retinal growth and patterning in the embryonic and post-embryonic (juvenile) zebrafish ptc2 mutant line. ptc2 deficiency in zebrafish results in an expansion of the stem/progenitor population of the ciliary marginal zone (CMZ), as well as ectopic proliferation within the neural retina at juvenile stages. ptc2-/- mutants also possess vitreo-retinal abnormalities that appear to be embryonic in origin. These phenotypes are similar to the ocular abnormalities previously reported in human patients suffering from Basal Cell Naevus Syndrome (BCNS), a disorder that has been linked to mutations in the human PTCH gene (the orthologue of the zebrafish ptc2), and point to the utility of the ptc2 mutant line as a model for the study of BCNS-related ocular pathologies. In addition, peripheral retinal dysplasias that include ectopic neuronal clusters and disrupted lamination were observed at later, juvenile stages. It has been previously proposed that retinal over-proliferation might contribute to retinal dysplasias observed in the post-natal Ptch1 /- mice (an established model for BCNS); however, this potential relationship has yet to be established experimentally. I demonstrated that a population of ectopically proliferating cells give rise to the ectopic neuronal clusters in the INL of ptc2-/- mutants and established ectopic proliferation as the likely cellular underpinning of retinal dysplasia in juvenile ptc2-/- mutants.