Transcriptional Dysregulation in Postnatal Glutamatergic Progenitors Contributes to Closure of the Cortical Neurogenic Period

Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency. Single-cell RNA sequencing reveals a dysregulation of transcriptional programs, which parallels changes in m6A methylation and correlates with the gradual decline in cortical neurogenesis observed in vivo. Rescuing experiments show that postnatal progenitors are partially permissive to genetic and pharmacological manipulations. Our study provides an in-depth characterization of postnatal Glu progenitors and identifies potential therapeutic targets for promoting brain repair. [Display omitted] •A large population of glutamatergic (Glu) progenitors persists in the postnatal SVZ•Postnatal Glu progenitors arise from a persistent population of radial glial cells•ScRNA-seq reveals transcriptional dysregulation in postnatal Glu progenitors•Changes in m6A methylation correlate with differentiation potential Donega et al. revisit the closure of the corticogenesis period by showing that a large population of glutamatergic progenitors remains in the postnatal SVZ. They show a dysregulation of transcriptional programs, which parallels changes in m6A methylation and correlates with a gradual decline in differentiation potential.