Forcing the amplification of neurons

"We asked ourselves whether the UPR had a physiological function for the control of this transition during corticogenesis", the scientist continues. "And this is indeed the case! We isolated the apical progenitors at different stages of development and we showed that there is indeed an UPR pathway that is more active at the beginning of corticogenesis. As the cortex continues to develop, this signalling pathway's activity diminishes". Hence, the UPR is very active during direct neurogenesis and is less so during indirect neurogenesis. In order to test the potential role of UPR in this balance between direct and indirect neuron production, the scientists targeted the UPR pathway early on. "We wanted to see whether this would alter the differentiative division capacity of stem cells because at this stage, almost all of them should produce neurons directly", Laurent Nguyen clarifies. "Well, if we reduce the intensity of the UPR pathway at the beginning of corticogenesis, the progenitor is forced to give birth to intermediate progenitors rather than a neuron!". Therefore, there is a physiological UPR pathway that controls the transition from direct neurogenesis behaviour to indirect neurogenesis behaviour. It is precisely the importance of the physiological UPR in controlling corticogenesis that the researchers revealed in an article published in the journal Trends in Neurosciences (1). They also gathered all related information concerning other systems such as the contribution of UPR in the development of drosophila neuroectoderm, the choice of receptors during the formation of the olfactory bulbs, etc. "There are many things in the literature that support the idea that a signalling pathway, which we believed was just a homeostatic response to stress, could actually play a key role in the development of the nervous system", Laurent Nguyen emphasises.  

UPR and foetal stress 

The scientists went one step further. The absence of Elongator creates foetal stress in mice, and foetal stress can be accompanied by microcephaly, as is the case in foetal alcohol syndrome, which affects some babies whose mother drank alcohol during the pregnancy. "These children have a flat midface, small eye openings, a short flat nose and, above all, microcephaly", Laurent Nguyen says. "Alcohol creates cellular stress which could also include stress in the endoplasmic reticulum in vivo. However, no-one has yet shown that the microcephaly in these children could result from a deregulation of the UPR signalling pathway. This is something that we are currently testing", he points out. Another line of research chosen by the scientists to test their model is that of foetal stress induced by viral infection. Starting out with purely fundamental research, the scientists have initiated more translational research. "It clearly shows the importance of funding non-oriented research", the researcher is keen to stress.

With these discoveries, Laurent Nguyen and his team have opened a very broad field of research in order to understand how UPR signalling is involved in the development of the nervous system. "Now it's a question of knowing what regulates this signalling pathway upstream. Is it stress or not? For now, we don't know how to connect the involvement of UPR upstream and downstream in brain development", Laurent Nguyen continues.

Defining the role of this signalling pathway could provide a new target in the long term for treatments against congenital disorders such as microcephaly, as well as various disorders of the nervous system. For instance, the UPR pathway is activated in the majority of neurodegenerative diseases such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis… 

(1) Godin J, Creppe C, Laguesse S, Nguyen L.. Emerging Roles for the Unfolded Protein Response in the Developing Nervous System. Trends Neurosci. 2016 Apr 26. pii: S0166-2236(16)30002-9. doi: 10.1016/j.tins.2016.04.002.