Both human and mice cortical RG can potentially produce OB interneurons. Mouse dorsal RG can retain their stemness to construct a part of SVZ in adult and produce OB interneurons migrating through RMS. Human dorsal RG can additionally and directly produce cortical inhibitory neurons (similar to those derived from CGE in ventral brain, defined here as IN.3 type) within the same clone coupled with excitatory neurons and glia. This is presumed to occur during embryonic stage by in vitro culturing fetal cells and lineage tracing them.
One interesting paper
Kohwi, M. et al. A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors. J. Neurosci. 27, 6878–6891 (2007).
but these progenitors are in LGE, and also experiments was down in adult mouse SVZ.
In the paper of mouse lineasge tracing, they found prenatal labeled RG can both produce EN and IN after postnatal. But ENs and INs are not in the same clone lineage. I guess this infer the adult neurogenesis of mouse RG can produce OB interneurons but not directly in embryonic stage.
From nowakowski paper
To determine the developmental potential of individual human cortical progenitors, we derived primary human cell cultures from the cortical germinal zone of three different specimens at stages of peak neurogenesis (gestational weeks 15 and 18, GW15 and GW18) (Fig. 1b). Before clonal labelling, one of the specimens (GW18) was further dissected on the basis of known anatomical landmarks, allowing us to generate region-specific cultures from the germinal zones of the prefrontal cortex (PFC), primary visual cortex (V1) and medial ganglionic eminence (MGE). They culture those primary tissue in vitro for 6 weeks before lineage analysis.
Transcriptome analysis of 121,290 cells identified three principal cortical cell type trajectories— excitatory neurons, GABAergic inhibitory neurons and glia—on the basis of differential gene expression, including that of marker genes NEUROD2, DLX2 and GFAP, respectively (Fig. 1c, d and Extended Data Figs. 2, 3). We identified intermediate progenitor cells (IPCs) within both the inhibitory and the excitatory neuron trajectories, which we refer to as DLX2+ IPCs (inhibitory trajectory) and EOMES+ IPCs (excitatory trajectory) (Extended Data Fig. 3). Cluster correlation analysis of STICR datasets with an scRNA-seq atlas of the developing primary human cortex at comparable developmental time points and regions14 further supported these cell-type designations (Extended Data Fig. 2d).
Iterative subclustering and transcriptional trajectory analysis of the inhibitory cells along with the DLX2+ IPCs revealed three distinct subgroups of GABAergic inhibitory neurons that we termed IN.1, IN.2 and IN.3 (Fig. 2d and Extended Data Fig. 5a–c). IN.1 cells were enriched for markers of SST+ cortical interneurons, including SST, NPY, TAC3 and NXPH1 (Fig. 2e). Consistent with developmental studies in mice which showed that SST+ cortical interneurons derive primarily from the MGE, 73% (492 of 671 cells) of IN.1 cells are produced by MGE progenitors (Extended Data Fig. 5d). Furthermore, MGE-derived IN.1 cells expressed canonical MGE-born interneuron genes, including LHX6, NKX2-1, ACKR3 (CXCR7), PDE1A and MAF, while cortically born IN.1 cells did not (Extended Data Fig. 5f). Together, these data suggest that IN.1 cells are transcriptionally similar to SST+ cortical interneurons and that the majority of IN.1 cells derive from the MGE. In contrast to IN.1 trajectory cells, IN.2 and IN.3 trajectory cells were transcriptionally similar to cells born from the caudal ganglionic eminence (CGE) based on their expression of marker genes such as SCGN, SP8, PCDH9 and BTG1 (Fig. 2e)18. Furthermore, IN.2 and IN.3 cells differed from IN.1 cells in that they were derived entirely from cortical progenitors, with no contribution from MGE progenitors (Extended Data Fig. 5d). Top IN.2 markers included TSHZ1, PBX3, MEIS2, CALB2, CDCA7L, SYNPR and ETV1, which are enriched in mouse olfactory bulb interneurons (Fig. 2f)19,20. By contrast, top IN.3 marker genes included NR2F1, NFIX, PROX1 and NR2F2,which are enriched within the CGE, as well as SOX6 and CXCR4, which are enriched in cortical interneurons (Fig. 2i), suggesting that these cells are transcriptionally similar to CGE-derived cortical interneurons14,21,22,23,24,25. Thus, although there are currently no marker genes that can unequivocally distinguish cortical interneurons from olfactory bulb interneurons, our transcriptome-wide data suggest that IN.2 cells resemble olfactory bulb interneurons while IN.3 cells are similar to CGE-born cortical interneurons.
Surprisingly, we found that most (79%; 655 of 829) multicellular clones that contained excitatory neurons also included putative cortical interneurons (IN.3 cells) (Fig. 2g), indicating that some human cortical progenitors can generate both excitatory neurons and cortical interneurons. Taken together, our results suggest that human cortical progenitors cultured in vitro are unexpectedly multipotent in their ability to generate a wide variety of principal neural cell types, including both excitatory neurons and putative cortical interneurons—two cell types previously thought to be produced by different pools of spatially restricted progenitors in the developing forebrain.
Notice the IN.3 neuron population
Unrelated: Clone analysis reveal cell number
In total, we identified 1,461 unique clonal barcodes, 1,324 of which belonged to multicellular clones with a median size of 23 cells per clone (Fig. 1e). Although there is very little known about the output of human cortical progenitors over this time scale, we observe a maximum clone size of 1,209 cells, which is congruent with a prior study that measured the output from three individual human outer radial glia.
Discussion
In a companion study34, STICR was used to perform in vivo clonal labelling of embryonic mouse forebrain progenitors, and STICR-labelled cells were analysed postnatally by scRNA-seq. Although both glutamatergic excitatory neurons and cortical GABAergic inhibitory neurons were recovered, they did not occur within the same clone. The lineage relationship that we observe between cortical excitatory and inhibitory neurons herein thus raises new questions regarding the development of the human cerebral cortex. First, what are the implications of a single progenitor producing both excitatory neurons and cortical interneurons? Evolutionary expansion of the primate neocortex has been attributed to the increased proliferative capacity of cortical neural progenitors. Adaptations in cortical progenitor competence to produce both principal types of cortical neuron could help to ensure the appropriate inhibitory/excitatory balance, despite the dramatic increase in the pool of cortical excitatory neurons35. Recent studies have revealed that although the inhibitory/excitatory balance increases from mice to humans, the relative composition of cortical interneuron types remains relatively constant across evolution. Although existing technical limitations prevent us from confidently estimating the precise cellular contributions of cortical progenitors to the mature human brain, future studies that quantify the relative contributions of progenitors from the cortex and ganglionic eminences will be helpful in understanding the cellular basis of how normal human cortical function is achieved.
Our study opens many avenues for future investigation. The molecular mechanisms that regulate the production of locally born cortical inhibitory neurons are unknown at present. In mice, signalling through the Sonic hedgehog pathway36 is required for individual cortical progenitors to undergo a GABAergic ‘switch’ and to generate inhibitory neurons37 that migrate to the olfactory bulb13. Does a similar molecular mechanism govern the production of cortically-derived cortical interneurons in humans? Furthermore, what molecular markers, if any, can distinguish them from cortical interneurons born in the CGE or MGE? Previous studies have found that NR2F1 and NR2F2 are expressed not only in the CGE but also in cortical progenitors9,10. Given the transcriptional similarity of cortically-derived IN.3 cells to CGE-derived interneurons observed here, it is possible that a similar developmental program is used. These are just some of the questions raised by our new understanding of the human cortical lineage, and addressing these will help to further decipher the origins and mechanisms underlying human brain development.
