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Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies
Mika Asai-Coakwell1, Lindsey March, Xiao Hua Dai
1Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada.
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.
Insights
Mutations in Growth Differentiation Factor 6 (GDF6) cause Leber congenital amaurosis and photoreceptor degeneration. A novel compound, P7C3, rescued retinal apoptosis in zebrafish models, suggesting new therapeutic avenues for retinal dystrophies.
Area of Science:
- Genetics
- Developmental Biology
- Ophthalmology
Background:
- Retinal dystrophies often stem from mutations impacting the phototransduction system and cilia.
- Identifying genes crucial for photoreceptor survival is vital for understanding and treating these conditions.
Purpose of the Study:
- To investigate the role of early embryonic retinal development growth factors in retinal dystrophies.
- To determine if mutations in Growth Differentiation Factor 6 (GDF6) are linked to Leber congenital amaurosis and photoreceptor degeneration.
Main Methods:
- Analysis of mutations in GDF6, a transforming growth factor-β (TGF-β) ligand.
- Utilizing murine and zebrafish mutant models to study gdf6 deficiency.
- Assessing the effect of P7C3, a novel compound, on retinal apoptosis in gdf6-deficient zebrafish.
Main Results:
- Mutations in GDF6 were identified as contributors to Leber congenital amaurosis.
- gdf6 deficiency led to photoreceptor degeneration and retinal apoptosis in animal models.
- Treatment with P7C3 successfully rescued retinal apoptosis in zebrafish without toxicity.
Conclusions:
- Perturbed TGF-β signaling, specifically involving GDF6, is implicated in the development of retinal dystrophies.
- GDF6 plays a role in photoreceptor survival.
- These findings suggest GDF6 and related morphogenetic genes as targets for retinal disease and offer potential therapeutic strategies beyond gene therapy.
