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

Neural progenitor cells lengthen their cell cycle to prime themselves for differentiation as development pro-ceeds. It is currently not clear how they counter this lengthening and avoid being halted in the cell cycle. We show that N6-methyladenosine (m6A) methylation of cell-cycle-related mRNAs ensures the proper cell-cycle progression of late-born retinal progenitor cells (RPCs), which are born toward the end of retinogenesis and have long cell-cycle length. Conditional deletion of Mettl14, which is required for depositing m6A, led to de-layed cell-cycle exit of late-born RPCs but has no effect on retinal development prior to birth. m6A sequencing and single-cell transcriptomics revealed that mRNAs involved in elongating the cell cycle were highly en-riched for m6A, which could target them for degradation and guarantee proper cell-cycle progression. In addition, we identified Zfp292 as a target of m6A and potent inhibitor of RPC cell-cycle progression.

Automated summary

Neural progenitor cells lengthen their cell cycle to prepare for differentiation, but it is unclear how they avoid being halted in the cell cycle. Our study shows that N6-methyladenosine (m6A) methylation of cell-cycle-related mRNAs ensures proper cell-cycle progression of late-born retinal progenitor cells. Conditional deletion of Mettl14, required for depositing m6A, delays cell-cycle exit of late-born RPCs, while having no effect on retinal development prior to birth. m6A methylation targets mRNAs involved in elongating the cell cycle for degradation and guarantees proper cell-cycle progression. Additionally, Zfp292 is identified as an m6A target and a potent inhibitor of RPC cell-cycle progression.