UPR helps overcome cellular stress 

While microcephaly can also be characterised by migration defects in the neurons, it is mainly due to an overall reduction in the number of neurons within the cortex. Either because the progenitors don't produce a sufficient amount of them, or because they have difficulty surviving. "Ultimately, the percentage of neurons is reduced and this leads to microcephaly", Laurent Nguyen continues. "These observations have allowed us to conclude that Elongator plays an important role in both types of cells: the progenitors and the neurons. Elongator is indeed involved in the neurons' ability to migrate and differentiate, and allows adequate production of neurons by the progenitors". When Elongator is no longer functional in the cortical wall cells and in particular in the progenitors, this causes cellular stress. "Molecular analyses clearly show signs of cellular stress that is conveyed through stress in the endoplasmic reticulum", the scientist adds. The endoplasmic reticulum (ER) is one of the organelles responsible for producing and modifying a large number of proteins in the cell. Stress can occur in the endoplasmic reticulum owing to the accumulation of misfolded proteins, for instance. The latter either have to be degraded or correctly refolded with the help of chaperone proteins. "That's where the Unfolded Protein Response (UPR) comes in", Laurent Nguyen explains. "This response will rectify the problem by producing chaperones to properly refold the proteins or by activating autophagy signalling pathways to get rid of the misfolded proteins".   

When the neurons go missing

So, to summarise: when Elongator is inactive, cellular stress occurs and the UPR pathway is activated. "However, excessive activation of UPR impairs neurogenesis", Laurent Nguyen reveals. "Stem cells with excess UPR activation will tend towards direct neurogenesis rather than indirect neurogenesis". This means that in the mouse's cortex, the apical progenitors surrounding the ventricle can give birth to neurons directly or indirectly. At the beginning of corticogenesis, the cells that divide will generate a stem cell and a neuron (direct neurogenesis). But as corticogenesis progresses and the need for neurons increases, these stem cells will choose another method of differentiative division. Rather than producing a neuron, they will tend to produce an intermediate progenitor that is able to proliferate before giving birth to neurons, ultimately amplifying the total number of neurons produced (indirect neurogenesis). "When Elongator doesn't function, there is a reduction in the pools of intermediate progenitors and the neuron amplifier is lost. That's why there are less neurons in the cortex in the end and this translates into microcephaly", Laurent Nguyen explains. 

The molecular mechanism that controls the choice of the stem cell's differentiative division was still unknown up until now. Why and how does this cell chooses to give birth to a neuron and a stem cell or an intermediate progenitor and a stem cell? The literature still provided no answer to this question.