title: Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies.
abstract: Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor-β (TGF-β) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-β signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.
authors: Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada.
authors: Mika
authors: M
authors: Asai-Coakwell
authors: Lindsey
authors: L
authors: March
authors: Xiao Hua
authors: XH
authors: Dai
authors: Michele
authors: M
authors: Duval
authors: Irma
authors: I
authors: Lopez
authors: Curtis R
authors: CR
authors: French
authors: Jakub
authors: J
authors: Famulski
authors: Elfride
authors: E
authors: De Baere
authors: Peter J
authors: PJ
authors: Francis
authors: Periasamy
authors: P
authors: Sundaresan
authors: Yves
authors: Y
authors: Sauvé
authors: Robert K
authors: RK
authors: Koenekoop
authors: Fred B
authors: FB
authors: Berry
authors: W Ted
authors: WT
authors: Allison
authors: Andrew J
authors: AJ
authors: Waskiewicz
authors: Ordan J
authors: OJ
authors: Lehmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D055431:Growth Differentiation Factor 6 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish
chemical_list: C525906:GDF6 protein, human; D055431:Growth Differentiation Factor 6