Ten-Eleven Translocation Enzymes Control the Rate and Mode of Retinal Progenitor Cell Division in the Developing...

Ten-Eleven Translocation (TET) enzymes are responsible for DNA demethylation and epigenetic regulation. Inactivation of TET enzymes in retinal progenitor cells (RPCs) leads to the emergence of a non-functional retina, resulting in blindness. However, it was not known how the inactivation of TET enzymes in RPCs affects their immediate function. To this end, we investigated TET-deficient RPCs in the developing retina using various approaches including EdU cell proliferation assay, immunohistochemistry, bulk RNA-seq, and snRNA-seq. We found that inactivation of TET enzymes in RPCs results in slow retinal growth. The number of dividing TET-deficient RPCs in these retinas is lower, whereas the number of non-dividing cells derived from them is significantly higher compared to controls. This phenomenon could be explained by the predominantly asymmetric division of TET-deficient RPCs, which is characteristic of late progenitor cells. At the same time, TET-deficient RPCs maintained a high rate of proliferation, continuing to divide even during late stages of retinal development, a phase during which cell division could no longer be detected in the control samples. A high rate of proliferation is a characteristic typically associated with early progenitor cells. We showed that retinas emerging from the activity of these TET-deficient RPCs are less developed and less complex, likely due to the mixed phenotype of the RPCs. Thus, our findings suggest that the activity of TET enzymes in RPCs is necessary to prevent mixing of their early and late phenotypes, a condition that is critical for normal retinal development.