Microcephaly is a brain malformation linked to a reduced number of neurons in the brain. It is a rare disease about which little is known. The GIGA-Neurosciences Research Unit of the University of Liege has just uncovered some of the mystery surrounding the genetic mechanisms that cause this under-development of the brain and the cerebral cortex in particular. They discovered that when a protein complex known as Elongator is absent from the stem cells of the cortex, these stem cells give rise to neurons mostly by direct means (direct neurogenesis), resulting in a reduced production of neurons by indirect means. They produce less intermediate progenitor cells by means of indirect neurogenesis, the role of which is to multiply the number of neurons. The consequence of this fate switch is that there will be fewer neurons in the cortex resulting in microcephaly. The discovery by the researchers at the University of Liege may contribute to the development of a treatment for this rare disease.  

Doctors are powerless against this kind of illness. However, diagnosis of the disease is not the problem. Very often microcephaly is detected during pregnancy by ultrasound but by then it is too late: this congenital malformation of the nervous system is not curable. Having a smaller brain is viable but may include slight intellectual impairment associated with epilepsy. There are many possible causes underlying microcephaly: genetic abnormality, consumption of alcohol during pregnancy, a viral infection in the mother…

Will it be possible to treat this disease in the future, as soon as it is detected in the embryo? “For now, the idea is still very much in the realm of science-fiction”, says a smiling Laurent Nguyen, a researcher at the FNRS and team leader at the Giga-Neurosciences Research Unit. “In any event, we are studying this idea and it certainly merits further investigation”! A lot will be revealed in the next few years. In the meantime, basic research has made it possible to uncover some of the mystery surrounding the molecular reasons for this malformation of the cortex. The results of this long-term project (the team from ULg has been working on this for five years) has just been published in the American journal Developmental Cell(1) and is part of ongoing research conducted on Elongator and an article published in the prestigious journal Cell in 2009.

Despite appearances to the contrary, the word Elongator does not refer to some American Science Fiction blockbuster featuring a muscle-bound hero. The term actually refers to a complex – a “group” of proteins – which is made up of 6 subunits, two of which are particularly important: “Elp1” whose role is to assemble the complex and “Elp3”, the enzymatic subunit which has the capacity to add an acetyl group to a molecule by acetylation of substrates.

It is caused by a defect

A small “development” defect during pregnancy can have heavy consequences. “We could compare it to an architect’s drawings”, says Laurent Nguyen by way of comparison. “If an error creeps in during the drawing up of plans, there is a risk that the building in question will be unstable or may even collapse. The same thing applies in genetics”. We know that a mutation in the coding gene for Elp1 leads to familial dysautonomia, a rare genetic disease characterised by problems of development and survival of certain neurons of the peripheral nervous system. The condition mainly affects the Ashkenazi Jewish population. Mutation of the Elp2 gene has recently been associated with intellectual disability, which is also characteristic of microcephaly patients. Mutation of Elp3 leads to amyotrophic lateral sclerosis, more commonly known under the name of Charcot’s disease, a neurodegenerative disease affecting the motor neurons.

In short, Elongator and its subunits are linked to the development and survival of neurons. In the first paper published in Cell in 2009, the team from the University of Liege demonstrated that it had an important role in the developing cortex. “Whenever we induced an acute reduction in the complex during corticogenesis (editor’s note: the process by which the cerebral cortex is constructed), we observed migration, maturation and differentiation defects in the projection neurons of the cortex”, recalls Laurent Nguyen. “On the other hand, we did not understand why the stem cells and the progenitor cells were left intact despite the expression of the complex in the latter”.  

A stem cell gives rise to neurons. This can happen either directly (this is known as direct neurogenesis, which occurs at the start of corticogenesis) or alternatively, the stem cell produces “intermediate progenitors” which function as amplifiers that serve to produce more neurons.

 (1) Sophie Laguesse et al., A dynamic unfolded protein response contributes to the control of cortical neurogenesis, Developmental Cell, décembre 2015