Mettl14-mediated m6A modification ensures the cell-cycle progression of late-born retinal progenitor cells
Liang Li,
Yue Sun,
Alexander E. Davis,
Sahil H. Shah,
Lobna K. Hamed,
Man-Ru Wu,
Cheng-Hui Lin,
Jun B. Ding,
Sui Wang
Affiliations
Liang Li
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Yue Sun
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA; Department of Neurosurgery, Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
Alexander E. Davis
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Sahil H. Shah
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Lobna K. Hamed
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Man-Ru Wu
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Cheng-Hui Lin
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
Jun B. Ding
Department of Neurosurgery, Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
Sui Wang
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA; Corresponding author
Summary: 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. 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 delayed 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 enriched 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.
