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

The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27^Kip1 plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27^Kip1 involve distinct activities, which are independent of its role in cell cycle regulation. p27^Kip1 promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27^Kip1 promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27^Kip1 plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.

Endocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of long-range axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB ₁ cannabinoid receptor (CB ₁ R) null and pyramidal cell-specific conditional mutant (CB ₁ R ^f/f,NEX-Cre ) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB ₁ Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.