Mettl14-mediated m6A modification ensures the cell cycle progression of late-born retinal progenitor cells

Abstract

Neural progenitor cells lengthen their cell cycle to prime themselves for differentiation as development proceeds. It is currently not clear how they counter this lengthening and avoid being halted in the cell cycle. Here, we show that m6A (N6-methyladenosine) methylation of cell cycle-related mRNAs ensures the proper cell cycle progression of late-born retinal progenitor cells (RPCs), which are born towards the end of retinogenesis and have long cell cycle durations. Conditional deletion of Mettl14, which is required for depositing m6A on mRNAs, significantly reduced the level of m6A modification in the developing mouse retina. This led to delayed cell cycle exit of late-born RPCs and neuronal cell death in mature retina, but appeared to have no effect on retinal development prior to birth. M6A-seq, which maps m6A modified mRNAs, and single cell transcriptomic analyses revealed that mRNAs involved in slowing down cell cycle progression were highly enriched for m6A modification, which could target them for degradation and guarantee proper cell cycle progression of late-born RPCs. In addition, we identified Zfp292 as a novel target of m6A and potent inhibitor of RPC cell cycle progression. Overall, our work establishes m6A modification as an important mechanism countering cell cycle lengthening in late-born retinal progenitor cells.