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

doi:10.1016/j.celrep.2023.112596

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

Cell Rep. 2023 Jun 27;42(6):112596. doi: 10.1016/j.celrep.2023.112596. Epub 2023 Jun 1.

Authors

Liang Li¹, Yue Sun², Alexander E Davis¹, Sahil H Shah¹, Lobna K Hamed¹, Man-Ru Wu¹, Cheng-Hui Lin¹, Jun B Ding³, Sui Wang⁴

Affiliations

¹ Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA.
² 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.
³ Department of Neurosurgery, Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA. Electronic address: suiwang@stanford.edu.

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. 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.

Keywords: CP: Developmental biology; CP: Neuroscience; Epitranscriptomic regulation; Mettl14; Zfp292; cell cycle; m(6)A mRNA methylation; retinal development; retinal progenitor cells (RPCs).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cell Differentiation
Cell Division
Neural Stem Cells*
Organogenesis
Retina* / metabolism

Abstract

Publication types

MeSH terms

Grants and funding