Radial glial cells are important in neuronal migration and also serve as neuronal progenitors, but signalling mechanisms among them are not well understood. Reporting in Neuron, Weissman and colleagues describe the discovery of a novel mechanism whereby proliferation of radial glial cells in the cortical ventricular zone (VZ) during development is regulated by spontaneous waves of calcium.

Using time-lapse calcium imaging, the authors first observed spontaneous calcium waves within the VZ of explants from the brains of embryonic day (E) 16–17 rats, which they could reproduce with electrical or mechanical stimulation. Calcium waves could be transmitted between two stimulated brain slices separated by up to 130 μm, indicating that the propagation might be mediated by diffusible signals.

By using various receptor antagonists, the authors found that extracellular ATP was involved in spontaneous and stimulated calcium waves. Direct application of ATP resulted in an increase in the intracellular calcium concentration of the VZ cells. Initiation and propagation of spontaneous and stimulated calcium waves occurred in the absence of extracellular calcium, but were reduced when intracellular calcium was depleted, indicating that the release of calcium from internal stores might have a crucial role in the initiation and propagation of calcium waves. This is consistent with the finding that inhibitors of either inositol triphosphate or Gq-phospholipase C (PLC) significantly attenuated calcium waves.

To determine which cells in the VZ are involved in calcium waves, Weissman and colleagues stimulated the E16 coronal brain slices with ATP and monitored the calcium waves in randomly selected cells using patch electrodes. They observed that most VZ cells that displayed calcium increases in response to ATP had radial glial morphology.

The authors then assessed the functional consequence of calcium waves in radial glial cells in the VZ. They found that the cells involved in calcium waves are located in the upper third of the VZ, which represents the S-phase zone (where most cells are in the S phase of the cell cycle). The expression of spontaneous and stimulated calcium waves is maximal at E16, when neurogenesis also peaks. This developmental profile of calcium waves correlates with the sensitivity of the VZ cells to ATP. When calcium waves in E16 brain slices were disrupted by an ATP-receptor antagonist, the incorporation of 5-bromo-2′-deoxyuridine by the VZ cells — an indication of DNA synthesis in the S phase — was significantly reduced. This defect in proliferation was rescued when calcium waves were restored by a PLC activator. The authors conclude that calcium waves modulate the proliferation of radial glial cells during development and, therefore, might be important in regulating the production of neocortical neurons.