Building blocks of the cerebral cortex: from development to the dish

Cells of the cerebral cortex. (a) Classification of established cell types in the cerebral cortex. These cells are broadly divided into neurons and glia. Neurons can be classified into glutamatergic projection neurons (PNs) and GABAergic interneurons, each of which is highly heterogeneous and can be subdivided into many different subtypes, according to morphological, molecular, and functional features. Glia can be divided into astrocytes, oligodendrocytes, and microglia, which can also be categorized into several subtypes. (b) Developmental origin of the various cortical cell types. (c) Selected cell type markers of PNs, interneurons, and glia. *Markers labeling a subset of the respective cell type. Abbreviations: CFuPN, corticofugal projection neuron; CThPN, corticothalamic projection neuron; SCPN, subcerebral projection neuron; CPN, callosal projection neuron; OPC, oligodendrocyte precursor cell; OL, oligodendrocyte; DVZ, dorsal ventricular zone; GE, ganglionic eminences.

In vitro generation of cortical cells. Strategies to differentiate cortical cell types in vitro follow similar developmentally inspired trajectories. Pluripotent cells, either embryonic or induced, form forebrain neuroepithelial cells even in the absence of factors. This default fate decision can be reinforced with FGF8 or dual SMAD/WNT inhibition. For directed differentiation of interneurons and oligodendrocytes, progenitors are ventrally patterned, while for astrocytes and projection neurons, progenitors are dorsally patterned. Once this regional specification is established, developmental programs unfold in typical order such that neurons are generated first, followed by astrocytes and oligodendrocytes. Different culture conditions and durations allow for enrichment of the desired population, although all strategies give rise to mixtures of neurons, glia, and progenitors. For cerebral organoids, pluripotent stem cells are grown in spinning bioreactors to allow natural developmental programs to unfold.

Schematic timeline of arrival of all major cell types in the cerebral cortex. The cortex is built through an intricately choreographed process that involves the integration of many different cell types. The cortex begins as a layer of neuroepithelial cells. Microglia from the yolk sac arrive early in development and invade the developing cortical plate. Projection neurons are generated in an inside out fashion beginning at E12.5. Interneurons migrate to the cortex from the ventral forebrain. Oligodendrocyte precursors arrive in the cortex in three waves from the MGE, LGE/CGE, and from within the cortex itself. Later in corticogenesis, progenitors initiate production of astrocytes. Abbreviations: IP, intermediate progenitor; NE, neuroepithelial cell; OL, oligodendrocyte; OPC, oligodendrocyte precursor cell; PV, parvalbumin; RG, radial glia; SST, somatostatin; 5HT3aR, serotonin receptor 3a; MGE, medial ganglionic eminence; LGE, lateral ganglionic eminence; CGE, caudal ganglionic eminence.