Dennis, D. J. | Search bioRxiv

bioRxiv2026

Single-cell multiomic approaches define a gradual, spatially-regulated epigenetic and transcriptional transition from embryonic to adult neural stem cells

Here, we ask how adult neural stem cells (NSCs) arise developmentally, focusing on murine cortical precursors that generate excitatory neurons embryonically and interneurons and glial cells postnatally. Using complementary single-cell spatial, transcriptomic, and epigenomic approaches, we show that postnatal NSC state acquisition involves a gradual transcriptional and epigenetic shift in the entire embryonic cortical precursor cell population and identify a distinct transition precursor state at E17/18 when both embryonic and the first postnatal progeny are being generated. Non-proliferative adult NSCs are also first seen at this transition timepoint, but they arise in a spatial domain distinct from that of the first postnatal progeny, indicating that NSC state acquisition is not a necessary prelude to the switch in cell genesis. These findings support a gradual epigenetically-continuous model for the transition from developing cortical precursors to NSCs and show that this is spatially separable from the transition to generating postnatal cell types.

developmental biology↗

bioRxiv2023

Proneural genes form a combinatorial code to diversify neocortical neural progenitor cells

Neocortical neural progenitor cells (NPCs) are molecularly heterogeneous, yet the genes that confer distinct neuronal morphologies and connectivities during development are poorly understood. Here, we determined that a proneural gene combinatorial code diversifies cortical NPCs. By mining scRNA-seq data from murine embryonic and early postnatal cortices and generating trajectory inference models, we found that Neurog2 is predominant, and is transiently co-expressed with Ascl1 and/or Neurog1 during an apical-to-basal NPC transition state in NPCs with early pseudotime identities. To assess whether proneural gene pairs confer distinct properties, we first used Neurog2/Ascl1 reporter mice expressing unique reporters, revealing that NPCs have distinct cell division modes and cell cycle dynamics dependent on their proneural gene profile. To assess Neurog2/Neurog1 interactions, we used double knock-out mice and novel split-Cre transgenics crossed to a Rosa-diptheria-toxin-A line to delete double+ cells, showing Neurog1/Neurog2 are specifically required to generate early-born neurons and to maintain NPCs. Finally, in silico mutation of a cortical Neurog2-gene regulatory network and validation using Neurog1/Neurog2 mutant and deleter mice, identified Bclllb and Nhlh2, expressed in early-born neurons, as dependent on Neurog1/Neurog2. Our data explains how proneural genes act combinatorically to diversify gene regulatory networks, thereby lineage restricting NPCs and creating cortical neuronal diversity.

developmental biology↗