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The secrets of microcephaly are revealed
12/8/15

Targeting Elongator

In 2009, the researchers from Liege were surprised that the genetic manipulation used to alter the expression of Elongator had consequences for the neurons but not their progenitors. “We then considered that the technological approach was probably not appropriate for analysing the progenitors”. Before that, the expression of Elongator was modified by “in utero electroporation” and this presented a problem: it made it possible to reduce the expression of the gene but not to make it disappear completely. “This residual activity might explain why there was no defect in the cortical progenitors. The latter probably do not need Elongator to be 100% present in order for them to function correctly, unlike neurons”, explains Laurent Nguyen. “Also, we were working at quite a late stage in cortical development. Perhaps we should have altered the expression of Elongator earlier”.

A change of method was necessary. The team created genetically-modified mice capable of making the Elongator activity “disappear” completely from its progenitors by means of the Cre-Lox recombination system. Quite unexpectedly, the invalidated mice presented with severe microcephaly!

The researchers discovered that when Elongator is absent from the stem cells of the cortex, these tend to go into “direct neurogenesis” mode exclusively. They therefore produce far less intermediate progenitors by indirect neurogenesis, the role of which is to multiply the number of neurons. The result of this is that there are no more neurons in the cortex resulting in microcephaly.

fter the mice, the experiment was repeated in flies. The results were the same. It then remained to confirm this in human stem cells, which was done with the help of stem cells taken from patients suffering from a mutation of the Elp1 gene. “We reprogrammed them with induced(2) pluripotent stem cells, which were grown in such a way as to model early brain neurogenesis. When Elp1 and Elp3 are not expressed correctly, these stem cells possess an affected neurogenesis programme which partially mimics the defect in the animal with microcephaly”.

Balance restored

Cortical wallWhether in humans, flies or mice the results were the same! An altered Elongator complex affects the balance between direct and indirect neurogenesis. But what was the mechanism behind this? This was the second phase of the research work. A molecular analysis by RNA sequencing coupled with an in-depth analysis showed that the absence of Elp3 led to stress in the endoplasmic reticulum that “part” of the cell made up of membrane tubules. This stress is first felt in the membrane of the endoplasmic reticulum. Then, different receptors transduce (that is to say, they respond by sending a signal) by means of a signalling pathway, which will ultimately reduce the impact of stress on the physiology of the cell. In other words, this signalling pathway will make it possible to correct the defect that caused the initial stress. “What is interesting, is the fact that by blocking transduction by means of genetic tools, thereby preventing the signalling pathway from being activated, we restore the neurogenesis balance”, points out Laurent Nguyen.

(2) Procedure which consists of genetically reprogramming an “adult” stem cell to give it the same properties as an embryonic stem cell. This technique, invented by Japanese professor Shinya Yamanaka, won him the Nobel Prize for medicine in 2012.

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