Retinal organoids as a valuable investigative tool to explore the role of Tau during retinogenesis.

The microtubule-associated protein Tau plays a crucial role in preserving the structure and function of neurons. During retinal development, tau is involved in growth, differentiation, and maturation of this neural tissue. However, the complex dynamic of retinogenesis makes it challenging to fully understand tau specific contributions. Furthermore, tau-associated mutations can result in the formation and accumulation of misfolded and aggregated proteins which disrupt normal cellular process and lead to retinal tissue damage. However, the specific molecular mechanisms and the direct sequence of events underlying this process remain poorly understood. Taking advantage of retinal organoids models, we investigated the tau-related changes during retinogenesis. We generated day 100 phase-bright retinal organoids using a human iPSC harboring an intronic IVS10+16 tau mutation (associated with Frontotemporal Dementia), and its isogenic control. We observed an imbalanced between the proliferation and differentiation of neuronal progenitor cells in mutant cultures during the first stage of retinal organoids generation (day 50), with a delayed induction of post-mitotic neurons. Furthermore, we confirmed an early and increased expression over the course of organoids generations of 4R tau isoforms in the mutant lines, leading to an altered 4R/3R isoform ratio. This finding results in increased Tau phosphorylation at specific sites in mutant organoids at day 100. In addition, at the final stage of mutant models, we observed a reduction in the expression of cytoskeleton proteins and synaptic markers. This decrease has implications for the formation and maintenance of synapses. Since tau helps the migration of retinal neurons in the appropriate layers to establish functional connections, we also improved the 3D imaging with clearing technique in order to visualize the integrity of retinal layers and the spatial organization of retinal cells. These results suggest that the inherited intronic tau mutation has a significant impact on retinal development and maturation. We can speculate that these changes may initially be compensated by homeostatic mechanisms. However, over time, the loss of these compensatory mechanisms can ultimately lead to retinal cells dysfunction and death.