FIGURE 2.

Schematic representation of the gradual shift from direct (left) to indirect (right) neurogenesis and of its imbalance after Zika infection in mammalian cerebral cortices. Briefly, at early stages of corticogenesis (from E10.5 to E13.5 in mice) apical progenitors (AP) populating the ventricular zone (VZ) of the rostral neural tube start producing first neurons, which will give rise to the primordial cortical plate (CP). At these stages the level of UPR is higher then later stages and gradually decreases as development proceeds. From E13.5 onward (in mice) AP start producing at least other two progenitor populations: basal progenitors and outer radial glia (not in the scheme) and, as UPR decreases, this neurogenic mode (called indirect) becomes gradually predominant. Indirect neurogenesis is only present in mammals (among all vertebrates) and mainly contributes to the amplification of the neuronal output during corticogenesis. Upon Zika infection, instead, UPR levels remain high also at later stages of development and the predominant mode of neurogenesis remains the direct one leading to a decrease in the total neuronal output and, hence, to a microcephalic cortex.