Unraveling the impact of tau on retinal development: Insights from human iPSC derived models of Frontotemporal Dementia

Tau, a microtubule-associated protein pivotal for neuronal integrity, is actively involved in retinal development, regulating growth, differentiation, and maturation processes. Mutations in Tau gene, MAPT, can lead to the formation of misfolded proteins, disrupting cellular processes and damaging tissue. Pathological hallmarks of tauopathies, such as Frontotemporal Dementia (FTD), have been identified in the retinas of patients in the early stages of pathology. However, the precise molecular mechanisms and the direct sequence of events underlying this process remain poorly understood. This study investigates the role of tau during neurogenesis by leveraging in vitro retinal models derived from human induced pluripotent stem cells (iPSCs) carrying an intronic IVS10+16 MAPT mutation associated with FTD and its isogenic control. This intronic mutation perturbs the finely regulated balance in the splicing of MAPT exon 10, inducing its inclusion and thus increasing the number of microtubule-binding domains present in the mature tau protein, which are more prone to phosphorylation. In this study, we highlight the critical role of tau in retinal development and suggest implications for neurodegeneration.