Abstract
During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia1,2. The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development. We quantified clonal divergence and convergence across all major cell classes postnatally, and found diverse types of GABAergic neuron that share a common lineage. Divergence of GABAergic clones occurred during embryogenesis upon cell-cycle exit, suggesting that differentiation into subtypes is initiated as a lineage-dependent process at the progenitor cell level.
Highlights
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]
We found that immediately after cell-cycle exit, GABAergic neurons that originated from the same mitotic progenitor diverged into different developmental trajectories
The STICR tag library was introduced via in utero injections into the lateral ventricles of mouse embryos at embryonic day 10.5 (E10.5; STICRE10), E12.5 (STICRE12), E13.5 (STICRE13) and E14.5 (STICRE14), stages that encompass the peak of neurogenesis
Summary
Asymmetrically dividing radial glia and transiently amplifying mitotic progenitors along the ventricular surface give rise to postmitotic neurons, astrocytes and oligodendrocytes[3,4,29,30,31,32] (Fig. 1d). Clusters ‘3 Astrocyte Slca12’ and ‘12a Astrocyte Ntrk2’ were both clonally related to clusters ‘6 Inhibitory neuron OB Synpr’ and ‘5a Excitatory neuron upper cortex’ (Fig. 2d, Extended Data Fig. 7), which suggests that distinct ventral and dorsal radial glia can give rise to transcriptomically similar astrocyte populations (Fig. 2e) Another example of convergence was OB neuroblasts (‘4 Inhibitory NP OB Ccnd2’) and dentate gyrus neuroblasts (‘17 Excitatory NP Sox11’), which occupied a single clade on the transcriptome dendrogram but distant clades on the lineage dendrogram (Fig. 2c). These data show that progenitor cells in the ganglionic eminences can produce daughter cells that traverse different developmental trajectories during peak neurogenesis This suggests that clonal divergence into different GABAergic precursor states is initiated at the level of mitotic progenitor cells and as a lineage-dependent process (Extended Data Fig. 10)
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