The actors involved in the fine-tuning of gene expression

Projection neurons have a complex radial migration. “At the beginning of corticogenesis, all neurons are attached to the surface of the brain. The implementation of the first cortical neurons is done by displacement of the nucleus, this is known as somal translocation”, explains Laurent Nguyen. “As the cortex increases in size, the projection neurons use a mixed mode of migration, but using mainly locomotion on the radial glia fibers (glial cells)”. The radial glia cables serve as a substrate, a little like rails so that the neurons can migrate by means of locomotion in order to reach their final position in the cortex. Once this goal is achieved, there is a change in the mode of migration: the neurons detached from the radial glial fibres, attach themselves to the interior surface of the cortex and move their nucleus into its final position. “During this process, the projection neuron goes from a multipolar shape in the form of a star to a bipolar shape, a form which it must absolutely acquire in order to adhere to the radial glial fibres and begin migration by means of locomotion”, indicates Laurent Nguyen. “This multipolar-bipolar transition of newly-born neurons is a rite of passage, an indispensable step so that migration can take place correctly”.  It sometimes happens that the regulation of this process fails and causes consequences such as lissencephaly for example.  As with many biological processes, the regulation of neuron migration can be done by means of genes, proteins or by epigenetics. “At this last level, we find microRNA, small non-coding RNA molecules that are capable of regulating the activity of certain genes by targeting their RNA messengers”, continues the researcher. “Currently we consider that 60% of our genes are regulated by microRNA. Epigenetic regulation enables a precise fine-tuning of gene expression”.

A technical challenge to be met

When Laurent Nguyen and his team began the present study, little was known about microRNAs in corticogenesis. “We wanted to try to decipher which microRNAs were important for the development of the cortex. One thing led to another and we decided to focus more specifically on neuronal migration and see if some microRNAs  fine-tuned the expression of genes that control this process?” Continues the scientist. This procedure represented a real technical challenge because we needed to be sure of analyzing the microRNAs and their target genes in the neurons and not in their progenitors. “We certainly know that microRNAs intervens in the control of the biology of stem cells and cortical progenitors. Altering microRNAs in the latter could have a secondary effect on the migratory behaviour of neurons”, states Laurent Nguyen. Thanks to a multi-disciplinary approach combining transgenic animals, in utero electroporation, analysis by time-lapse (confocal microscopy coupled with real time imaging) and microarray (DNA chip), the researchers succeeded in meeting the challenge and identifying two microRNAs that target the CoREST  gene: miR-124 and miR-22. “CoREST is part of a complex of transcription inhibition one of whose targets is the doublecortin gene known to be crucial in projection neuron migration”, explains Lauren Nguyen. Put simply: in the absence of miR-22 and/or miR-124, the researchers observed an increase in the expression of the CoREST gene, and therefore a strengthening of the inhibition of the transcription of the doublecortin gene, which causes a deregulation of projection neuron migration. “This is the first time that the importance of some microRNAs in the control of genes involved in this migration has been demonstrated”, reveals Laurent Nguyen.