The secrets of microcephaly are revealed
Targeting ElongatorIn 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”. Balance restoredWhether 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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© 2007 ULi�ge
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