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<p>Mutations in <i>ABCA4</i> gene causes Stargardt macular degeneration, which manifests with toxic lipofuscin deposits in the outer retina, gradual atrophy of RPE cells, followed by photoreceptor cell loss. The cone-enriched retina, with macula-like ‘area-temporalis’ of zebrafish are better models than rodents for studying human macular dystrophies. Here, we generated <i>abca4b</i> knockout zebrafish model using CRISPR/Cas9 editing and evaluated the early and late-stage retinal changes. In adult <i>abca4b</i><sup><i>−/−</i></sup> mutants, the RPE cells exhibited hyperpigmentation, altered retinomotor behaviour and lipofuscin accumulation, but they remained viable. However, the photoreceptors underwent progressive degeneration, with a sequential loss of blue and UV cones, followed by red and green cones and finally the rod cells. This triggered the chronic activation and early depletion of retinal stem cells at the ciliary marginal zone of mutants and resulted in accelerated outer-retinal degeneration and severe visual defects, despite them retaining the Müller glia-dependant retinal repair potential.</p>

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Loss of retinal stem cell reserve and lipofuscin accumulation accelerates cone-rod degeneration and replicates Stargardt disease in abca4b null zebrafish

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Divya Pidishetty,
  • Santhosh Kumar Damera,
  • Murali Murugavel,
  • Praveen Joseph Susaimanickam,
  • Sai Naga Sri Harsha Chittajallu,
  • Gopal Kushawah,
  • Puja Sarkar,
  • Shrikant R. Bharadwaj,
  • Rakesh Mishra,
  • Indumathi Mariappan

摘要

Mutations in ABCA4 gene causes Stargardt macular degeneration, which manifests with toxic lipofuscin deposits in the outer retina, gradual atrophy of RPE cells, followed by photoreceptor cell loss. The cone-enriched retina, with macula-like ‘area-temporalis’ of zebrafish are better models than rodents for studying human macular dystrophies. Here, we generated abca4b knockout zebrafish model using CRISPR/Cas9 editing and evaluated the early and late-stage retinal changes. In adult abca4b−/− mutants, the RPE cells exhibited hyperpigmentation, altered retinomotor behaviour and lipofuscin accumulation, but they remained viable. However, the photoreceptors underwent progressive degeneration, with a sequential loss of blue and UV cones, followed by red and green cones and finally the rod cells. This triggered the chronic activation and early depletion of retinal stem cells at the ciliary marginal zone of mutants and resulted in accelerated outer-retinal degeneration and severe visual defects, despite them retaining the Müller glia-dependant retinal repair potential.