Non-canonical telomere repeat-binding factor 2 control of retinal development

Telomere repeat-binding factor 2 (TRF2) protects chromosome ends but also regulates extra-telomeric chromatin structure and function. Using zebrafish mutants, we show that complete loss of the gene encoding TRF2 (terfa) spares early retinal progenitor expansion yet later causes catastrophic Müller glia failure, loss of retinal lamination, genome-wide DNA damage and apoptosis. The eyes of heterozygous zebrafish (terfa+/-) exhibit preserved gross structure, but Müller glial scaffolding is disrupted, Pax6-derived lineages are reduced and retinal transcriptional programmes are altered without detectable DNA damage, with a subset of phototransduction and regulatory genes remaining mis-regulated in adult eyes. These findings identify TRF2 as a dosage-sensitive, non-canonical regulator of retinal development whose dysfunction reprogrammes retinal transcriptional circuits, suggesting that coupling telomere and genome stability to sensory organ development shapes visual resilience and vulnerability to ageing. This article is part of the theme issue 'Developmental circuits in ageing'.