We found that immediately after cell-cycle exit, GABAergic neurons that originated from the same mitotic progenitor diverged into different developmental trajectories. We focus our analysis on GABAergic neurons, which displayed a surprising degree of clonal divergence among different types of inhibitory neurons. Here we combined high-throughput single-cell RNA sequencing (scRNA-seq) with massively parallel tagging of progenitors to reconstruct lineage relationships during neurogenesis of the forebrain. More recently, breakthroughs in cellular barcoding strategies and single-cell sequencing 13, 14, 15, 16, 17, 18, 19, 20, 21 have facilitated the recording of lineage tags and gene expression profiles in in vitro systems 22, in zebrafish 20, 23, 24 and in mouse embryogenesis 25, but have not yet been used to study neurogenesis in the mouse forebrain. The extent to which developmental trajectories are predetermined by specified progenitor lineages during mitotic stages, or emerge through interactions with the environment later in development, remains an open question.Īlthough previous lineage analyses have elucidated the spatial distribution of clones, they provided little information regarding subtype identities of sister cells 8, 9, 10, 11, 12. Transcriptional signatures that distinguish mature neuronal subtypes emerge only after cell-cycle exit and become more sharply defined during postnatal development 1, 2, 5, 6, 7.
During development, molecular diversity is initially reflected in the regional expression of a narrow set of transcription factors in mitotic progenitors 3. The central nervous system consists of diverse types of neurons and glia that vary widely in morphology, physiology, connectivity and molecular markers 3, 4.