| First Author | Moffat A | Year | 2024 |
| Journal | bioRxiv | Mgi Jnum | J:346003 |
| Mgi Id | MGI:7612303 | Doi | 10.1101/2023.07.29.551096 |
| Citation | Moffat A, et al. (2024) Proneural genes form a combinatorial code to diversify neocortical neural progenitor cells. bioRxiv |
| abstractText | 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 âdeleterâ 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. |
