Single-cell transcriptional logic of cell-fate specification and axon guidance in early-born retinal neurons.

Retinal ganglion cells (RGCs), cone photoreceptors (cones), horizontal cells and amacrine cells are the first classes of neurons produced in the retina. However, an important question is how this diversity of cell states is transcriptionally produced. Here, we profiled 6067 single retinal cells to provide a comprehensive transcriptomic atlas showing the diversity of the early developing mouse retina. RNA velocities unveiled the dynamics of cell cycle coordination of early retinogenesis and define the transcriptional sequences at work during the hierarchical production of early cell-fate specification. We show that RGC maturation follows six waves of gene expression, with older-generated RGCs transcribing increasing amounts of guidance cues for young peripheral RGC axons that express the matching receptors. Spatial transcriptionally deduced features in subpopulations of RGCs allowed us to define novel molecular markers that are spatially restricted. Finally, the isolation of such a spatially restricted population, ipsilateral RGCs, allowed us to identify their molecular identity at the time they execute axon guidance decisions. Together, these data represent a valuable resource shedding light on transcription factor sequences and guidance cue dynamics during mouse retinal development.

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.