m6A regulation of cortical and retinal neurogenesis is mediated by the redundant m6A readers YTHDFs
Fugui Niu,
Pengfei Che,
Zhuoxuan Yang,
Jian Zhang,
Lixin Yang,
Mengru Zhuang,
Xijun Ou,
Sheng-Jian Ji
Affiliations
Fugui Niu
Harbin Institute of Technology, Harbin, Heilongjiang 150001, China; School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; SUSTech-HIT Joint Graduate Program, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Pengfei Che
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Zhuoxuan Yang
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Jian Zhang
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Lixin Yang
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Mengru Zhuang
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Xijun Ou
School of Life Sciences, Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Corresponding author
Sheng-Jian Ji
School of Life Sciences, Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Corresponding author
Summary: m6A modification plays an important role in regulating mammalian neurogenesis. However, whether and how the major cytoplasmic m6A readers, YTHDF1, YTHDF2, and YTHDF3 mediate this process is still not clear. Here, we demonstrate that Ythdf1 and Ythdf2 double deletion but not individual knockout recapitulates the phenotype of Mettl14 knockout in cortex. In addition, we find that Mettl14 knockout in retina causes protracted proliferation of retinal progenitors, decreased numbers of retinal neurons, and disturbed laminar structure. This phenotype is only reproduced when Ythdf1, Ythdf2, and Ythdf3 are knocked out simultaneously in retina. Analysis of YTHDF target mRNAs in mouse cortex and retina reveals abundant overlapping mRNAs related to neurogenesis that are recognized and regulated by both YTHDF1 and YTHDF2. Together our results demonstrate that the functionally redundant YTHDFs mediate m6A regulation of cortical and retinal neurogenesis.
