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

Abstract

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 mA 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.

Temporal Embryonic Origin Critically Determines Cellular Physiology in the Dentate Gyrus

“…Dentate granule cells are the principal components of the dentate gyrus (DG), which is the critical entry point to the hippocampus. Much attention has been given to adult neurogenesis in this region because it is 1 of only 2 brain areas where it occurs in nonhuman mammals and in particular in rodents (Donega et al 2018). The continuous addition of new granule cells in rodents makes the DG a highly heterogeneous structure composed of different generations of neurons.…”

Contributions of Single-Cell Approaches for Probing Heterogeneity and Dynamics of Neural Progenitors Throughout Life: Concise Review

“…This goes in line with the different dynamics observed in the generation of pallial (i.e., TBR2+) and subpallial (i.e., DLX2+) progenitors observed at postnatal stages. Thus, although TBR2 progenitors continue to be produced by pallial RGs at early postnatal time points [38], their production rapidly decreases over time to become almost extinguished by P90 [57]. On the contrary, DLX2+ progenitors continue being produced throughout adulthood, in agreement with the preferential accumulation of quiescent NSCs in the lateral SVZ [53].…”

“…Interestingly, recent clonal fate mapping suggests that this neurogenic to gliogenic transition is largely incomplete, as only a fraction of RG cells (estimated to roughly 1/6), switch to produce glial cells [13]. Other pallial RGs appear to continue producing IPCs (TBR2/NEUROG2 positive), whose contribution to cortical neurogenesis rapidly declines postnatally [38](see https://genebrowser.lyon.inserm.fr/ for related transcriptional changes).…”

“…Other epitranscriptomic changes mediating temporal control over lineage progression, include m6A methylation, recently suggested to regulate transcription in NSCs self-renewal [50], as well as in the temporal control of corticogenesis [51]. The observation of a large decrease in m6A level in cortical progenitors persisting at birth suggests that epitranscriptomic modifications participate in the closure of the period of cortical neurogenesis [38]. Taken together, these studies highlight that the temporal production of defined neuronal subtypes is the result of numerous regulating mechanisms, not restricted to the mRNA expression revealed by scRNA-Seq, but also including post-translational mechanisms, including regulation of protein translation.…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…Approximately 1 in 6 RGCs switches to gliogenesis, generating astrocytes and oligodendrocytes at the end of the cell cycle [133]. The process of neuroprogenitor specification during corticogenesis has been studied and reviewed in great detail elsewhere (see [134] or for a review see [116]) and will therefore not be discussed in this review. Numerous studies however have shown that defects in chromatin remodelers during RGC specification result in shifts in the neuron classes produced or in precocious cell cycle exit and gliogenesis, and thereby could contribute to the neuronal phenotypes found in NDD patients [135].…”