SUMMARY N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to prolonged cell cycle and maintenance of radial glia cells. m6A-sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, cell cycle and neuronal differentiation, and m6A-tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional pre-patterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A-tagging of transcripts related to brain disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

Graphical AbstractHighlights d The Hopx-CreER T2 line can label an embryonic origin of adult dentate neural progenitors d Hopx + dentate progenitors exhibit constant lineage specification across development d Developmental and adult dentate neurogenesis are one continuous process d Hopx + dentate progenitors retain common molecular signatures across development SUMMARY New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx + precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx + neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx + quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx + embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a ''continuous'' model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.

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Over the past few decades, major advances have been made in identifying the origins of cardiac cells from developing embryos. In particular, the discovery of the first heart field (FHF) and the second heart field (SHF), led us to understand how diverse lineages and different anatomical structures of the heart arise during cardiogenesis. However, it remains unknown how the two heart fields are specified and segregated, a fundamental step toward understanding heart formation and developing pluripotent stem cell (PSC)-based therapeutic strategies. Here, we generated 3D organoids with mouse PSCs that harbor green and red fluorescent protein (GFP and RFP) reporters under the control of the FHF marker Hcn4 and the SHF marker Tbx1 , respectively. We demonstrate how GFP+ cells and RFP+ cells appear from two distinct areas of mesodermal cells and develop in a complementary fashion, similar to the in vivo process. Consistently, these populations exhibit a high degree of similarities with FHF/SHF cells isolated from early embryos, determined by RNA-sequencing analysis. Through a series of bioinformatics approaches, we found that Bmp and Wnt are among the most differentially regulated pathways in the two populations. Importantly, an increased activity of Bmp or Wnt signaling resulted in selective induction of GFP+ or RFP+ cells from mesodermal cells, enabling us to generate heart field-specific cells from PSCs. We further found that FHF/SHF cells can be distinguished and isolated by the surface proteins CD184 and EphA2. This study provides fundamental insights into understanding the specification of two cardiac origins that enable generation of chamber-specific populations for studying heart field/chamber-specific heart disease in cell culture.