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Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex

Origins of neuronal diversity Although the main task of a neuroprogenitor is to produce more cells, it may not always produce the same cells. Some progenitors produce different daughter neurons as an embryo develops. Concurrently, these daughter neurons are also transitioning through states toward maturation. Telley et al. used single-cell RNA sequencing to survey the transcriptional identity of cells early in mouse brain development. As a neuroprogenitor transitioned to new states, it produced daughter neurons that reflect those new states. The neuron's own postmitotic differentiation program is apparently overlaid onto these parentally supplied programs, driving emergence of specialized neuronal cell types in the neocortex. Science, this issue p. eaav2522 During corticogenesis in the brain, temporally dynamic molecular birthmarks in progenitors act as seeds for later neuronal diversity. INTRODUCTION The cerebral cortex is a cellularly heterogeneous structure whose neuronal circuits underlie high-order cognitive and sensorimotor information processing. Neocortical neuronal diversity emerges from interactions between intrinsic genetic programs and environment-derived signals, but how these processes unfold and interact in the developing brain is still unclear. During embryogenesis, distinct subtypes of glutamatergic neurons are sequentially born and differentiate from progenitors located in the ventricular zone below the cortex. The aggregate neurogenic competence of these ventricular zone progenitors (i.e., apical progenitors) hence progresses as corticogenesis proceeds, and temporal molecular patterning is thought to be a driving force for this process. Such temporal patterning is an evolutionarily conserved strategy to generate neuronal diversity, but in contrast to Drosophila, in which key molecules of temporal specification have been identified, how this occurs in mammals remains poorly understood. RATIONALE Although the cell type diversity of the adult neocortex is increasingly well characterized, how pre- and postmitotic developmental molecular programs unfold and interact during development remains unknown. This in part reflects our limited ability to assess molecular states at defined time points and in specific cell types with high temporal resolution. Here, we overcame this obstacle by combining FlashTag, a method to pulse-label isochronic cohorts of ventricular zone–born neurons and their mother cells, with single-cell RNA sequencing. Using this approach, we traced the transcriptional trajectories of successive generations of apical progenitors and their respective daughter neurons in mice from embryonic day 12 to day 15, as layer 6, 5, 4, and 2/3 neurons are successively generated. RESULTS Using temporal analysis of apical progenitor molecular states, we identified a core set of evolutionarily conserved, temporally patterned genes that sequentially unfold during development. These dynamically expressed genes drive apical progenitors from internally directed (“introverted”) to more exteroceptive (“extraverted”) states. Initially, cell cycle–related and nucleus/chromatin–related processes are prominent activities. Later in development, the susceptibility of apical progenitors to environmental signals increases, as highlighted by increased expression of membrane receptors, cell-cell signaling–related proteins, and excitability-related proteins. Temporally patterned genes are transmitted from apical progenitors to their neuronal progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied. This process is evolutionarily conserved, because in human embryos, the transcriptional dynamics of the orthologs of this gene set are recapitulated in apical progenitors and their daughter neurons. Whereas acquisition of ground states by daughter neurons is largely environment-independent, cell-extrinsic processes come into play at later stages to sculpt final identity, as demonstrated by the progressive loss of apical progenitor–derived molecular birthmarks and the emergence of input-dependent transcriptional programs. This was particularly striking for differentiating layer 4 neurons, whose postnatal development strongly depends on synaptic input, suggesting that environmental sensibility may be prefigured prior to sensory experience. Finally, using a loss-of-function approach, we demonstrate that the temporal progression in apical progenitor states is epigenetically regulated by the Polycomb repressor complex PRC2, such that loss of PRC2 leads to an acceleration of apical progenitor neurogenic competence, as revealed by precocious generation of normally later-born cell types. CONCLUSION Our work provides a functional account of molecular programs at play in apical progenitors and their daughter neurons during corticogenesis in mice, and reveals that epigenetically regulated temporal molecular birthmarks in apical progenitors act in their postmitotic progeny as seeds for neuronal diversity. Conserved differentiation programs, together with later-occurring environment-dependent signals, then act on these sequential ground states to drive newborn neurons toward their final, cell type–specific identities. Temporal molecular patterning in the mouse neocortex. Evolutionarily conserved, temporally patterned genes drive apical progenitors from internally directed to exteroceptive states. The PRC2 complex epigenetically drives this progression (not shown). Embryonic age–dependent molecular marks are transmitted from apical progenitors to newborn neurons as successive ground states, onto which essentially conserved differentiation programs are applied, together with later-occurring environment-dependent signals. Thus, temporal molecular birthmarks in progenitors act in their postmitotic progeny to seed adult neuronal diversity. During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age–dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.