Neurogenesis and Cellular Mechanisms in Cortical Development

The mammalian cerebral cortex arises from a neuroepithelial sheet that expands through successive rounds of progenitor division and differentiates into the six-layered structure responsible for higher cognitive functions. Radial glial progenitors serve as both scaffolds and neural stem cells, undergoing symmetric and asymmetric divisions to produce neurons directly or via intermediate basal progenitors. Newly born neurons migrate along radial fibres to their laminar destinations, where cell–cell interactions, signalling gradients and epigenetic programmes refine their identity and connectivity. Transcription factors and cis-regulatory elements orchestrate progenitor fate decisions, while epigenetic barriers establish the temporal pace of neuronal maturation. Inhibitory GABAergic interneurons arise from distinct ganglionic eminences, guided by enhancer landscapes that specify projection versus interneuron identity. The coordinated interplay of proliferation, differentiation, migration and maturation underpins cortical expansion across species and its perturbation underlies developmental disorders. Understanding these cellular mechanisms informs strategies for regenerative therapies, in vitro modelling and the diagnosis of malformations that contribute to intellectual disability, epilepsy and autism spectrum conditions.

Research from Nature Portfolio

Recent studies have uncovered an intrinsic epigenetic barrier in human pluripotent stem cell-derived cortical progenitors that sets the prolonged timeline of neuronal maturation. Inhibition of specific histone-modifying enzymes at the progenitor stage releases transcriptional programmes and accelerates functional properties in newly born neurons, demonstrating that maturation rate is predetermined before neurogenesis. Complementary work in the mouse ganglionic eminence has revealed how the transcription factor MEIS2, in cooperation with DLX5 or repressed by LHX6, binds to cell-type-specific enhancers to bias progenitors towards projection neurons or interneurons. This differential enhancer activation model elucidates the molecular logic by which interneuron identity is sculpted during embryonic development.

Neurogenesis and Cellular Mechanisms in Cortical Development publication trend

The graph below shows the total number of articles in neurogenesis and cellular mechanisms in cortical development across all publications each year (not limited to Nature Index journals).

Technical terms

Neurogenesis: The process by which neural stem or progenitor cells generate new neurons.

Radial glial progenitor (RGP): A neural stem cell in the ventricular zone that gives rise to neurons and glia.

Basal progenitor: An intermediate progenitor in the subventricular zone that amplifies neuron production.

Epigenetic barrier: A chromatin-based mechanism that delays activation of maturation-related genes.

Enhancer: A cis-regulatory DNA element that increases transcription of target genes in a cell-type-specific manner.

GABAergic interneuron: A cortical inhibitory neuron releasing γ-aminobutyric acid to modulate excitatory circuits.

References

1. An epigenetic barrier sets the timing of human neuronal maturation. Nature (2024).
2. Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development. Nature Neuroscience (2024).
3. Deterministic Progenitor Behavior and Unitary Production of Neurons in the Neocortex. Cell (2014).
4. 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Cell Stem Cell (2016).
5. New insights into the development of the human cerebral cortex. Journal of Anatomy (2019).