The hidden side of the UPR signalling pathway
Initially recognized as homeostatic signalling pathway that helps cells to cope with cellular stress, the Unfolded Protein Response (UPR) has kept an unexpected activity well hidden up until now. It would also seem that it plays an important physiological role in the development of the nervous system. That's what Laurent Nguyen and his team reveal in an article published in Trends in Neurosciences.
Pregnancy and monitoring the foetus' development arouses feelings of both excitement and apprehension of future parents. Is it growing well? Is it still moving? Are its limbs well formed? Is its brain developing properly? In the majority of cases, the news is good and the baby is developing properly. Sometimes, parents are increasingly filled with doubts until the moment their child arrives. In other cases, the pregnancy can be associated with bad news: the child isn't viable or is suffering from a serious malformation. During scans, particular attention is paid to the nervous system and especially the brain, which are regularly measured and checked. The highly complex development of the nervous system is well understood overall but there are still many grey areas regarding the mechanisms that govern the workings of this sophisticated machinery. And it is these grey areas that Laurent Nguyen's team is endeavouring to clarify by studying the differentiation and the migration of the neurons in the cortex. In 2009, the researchers from Liège, along with Alain Chariot's team, showed that the Elongator complex played an important role in the migration and differentiation of the neurons in the cortex (see article Neuron migration "under the wing" of Elongator). What they didn't realise at the time was that this discovery would lead them to pin down the mechanism which, unbeknown to them up until now, plays a role in the early stages of the cerebral cortex's development.
The absence of Elongator and microcephaly
"While we were working on Elongator, we used the in utero electroporation technique to reduces the expression, and therefore activity, of Elongator in a limited number of cortical cells", explains Laurent Nguyen, Director of the Laboratory of Molecular Regulation of Neurogenesis, GIGA-Neurosciences. "What's surprising is that Elongator is expressed through the cortical wall starting from the progenitors, along the ventricle, up to the neurons which are in the process of migrating and differentiating. However, with in utero electroporation, we observed that the reduction in Elongator expression modified the migration and differentiation of the neurons without impairing the biology of the cortical progenitors". Although Elongator is expressed in the cortex's progenitors and stem cells, why does reduced Elongator activity only affect the behaviour of the neurons? That's the question the scientists wanted to find an answer to. "We used another strategy: transgenic mice in which the absence of the enzymatic subunit of the Elongator complex abolished the activity of this complex in both the stem cells and neurons in the cortex", Laurent Nguyen points out. The mice in question didn't "only" present a migration and differentiation defect in the cortical neurons, as is the case in rodents that have been subjected to in utero electroporation. The transgenic mice were far more severely affected: they suffered from microcephaly. "This is what we showed in an article published in October 2015 in Developmental Cell, a Cell Press journal", the researcher elaborates (see article The secrets of microcephaly are revealed).