MRC National Institute for Medical Research, London
Science for Health
Master control of neuronal migration
07 August 2008
The formation of the brain involves the production of many different kinds of neurons that must be positioned very precisely so that they can contact other neurons and integrate into functional neuronal circuits. New neurons are always generated at a distance from their final locations and they must travel along very specific routes in the developing brain to reach these locations. This process of neuronal migration is of considerable importance for the correct development of the brain. Mutations in genes that cause migration defects in the cerebral cortex during foetal life often result in severe mental retardation.
The mechanisms determining when new neurons should start migrating have remained unclear. We have found that the gene Rnd2, which codes for a divergent small GTP-binding protein, is expressed by migrating neurons of the cerebral cortex in mouse embryos, and its expression is initiated just before migration begins. Blocking Rnd2 expression in neuron progenitors by introducing small interfering RNAs prevented neuronal migration, thus establishing Rnd2 as an important regulator of this process. We have also shown that expression of the Rnd2 gene in neuronal progenitors is induced by the proneural transcription factor Neurogenin2, a master regulator of the neurogenic programme in the developing cerebral cortex. Deleting the Neurogenin2 gene in new neurons prevents their migration, and we have shown that forcing Rnd2 expression in Neurogenin2-mutant neurons was sufficient to rescue their migration defect. Rnd2 is therefore the main regulator of neuronal migration in the developmental programme activated by Neurogenin2 in the cerebral cortex. The direct regulation of a small GTP-binding protein by a proneural protein explains the tight coupling that is found between the birth of neurons and their migration.
Different proneural transcription factors promote neurogenesis in different brain regions. Interestingly, Rnd2 is not expressed by all migrating neurons but only by those under the control of Neurogenin2. The related Rnd3 gene is induced in other neurons by another distinct proneural transcription factor, known as Mash1. This raises the exciting possibility that a protein code involving the sequential activation of Rnd proteins by these master regulators of neurogenesis controls different modes of neuronal migration by newborn neurons in the developing brain.
We did not expect that a complex cellular process such as neuronal migration would be initiated by a very simple pathway, involving a transcription factor and its direct target, a small GTP-binding protein. The challenge is now to find out whether this pathway contributes to the huge diversity of migratory behaviours that are observed in the developing brain
Dr François Guillemot
Original article
The research findings are published in full in:
Julian Ik-Tsen Heng, Laurent Nguyen, Diogo S. Castro, Céline Zimmer, Hendrik Wildner, Olivier Armant, Dorota Skowronska-Krawczyk, Francesco Bedogni, Jean-Marc Matter, Robert Hevner & François Guillemot
Neurogenin 2 controls cortical neuron migration through regulation of Rnd2
Nature, Epub ahead of print Publisher abstract
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