The secrets of microcephaly are revealed
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. It is caused by a defectA 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”. ![]() (1) Sophie Laguesse et al., A dynamic unfolded protein response contributes to the control of cortical neurogenesis, Developmental Cell, décembre 2015 |
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