Researchers from IBEC and the University de Barcelona (UB), in collaboration with the Institute of Marseille Luminy, University of the Mediterranean in France and the Cincinnati Children’s Hospital, USA, have identified for the first time a new molecular mechanism regulating the migration of Cajal-Retzius cells in the early stages of development of the cerebral cortex, the outermost layer of the brain.
The distribution of Cajal-Retzius cells in the cortex is essential because, in humans, if there are alterations in distribution or no expression of some of the molecules produced by these cells, lissencephaly will develop, a disease in which the cortex is smooth, without convolutions, leading to mental retardation and impaired control of movements.
Cajal-Retzius cells are generated in three different parts of the brain, and during the initial stages of its development, these cells migrate in parallel to the brain surface in order to cover the entire surface of the brain cortex with what’s known as ‘layer I’. These cells play a critical role in the migration of neurons in the cerebral cortex and the subsequent formation of the different layers that form it. They must migrate in a coordinated manner across layer I, which requires the correct molecular signalling to guide them to their destination. The migration of Cajal-Retzius cells is also regulated by a molecular attraction system, the CXCL12/CXCR4. This system is essential for attracting cells from their origin points to the cerebral cortex surface, but, by itself, it cannot tell them when to stop migrating to complete its distribution throughout the cortex.
In their study, published today in Nature Communications, the researchers demonstrate for first time the existence of a signaling molecule, Semaphorin 3E (Sema3E), which, by joining PlexinD1 (its specific receptor present in Cajal-Retzius cells) is able to modulate the action of the CXCL12 / CXCR4 system.
“The Sema3E/PlexinD1 system indicates when the Cajal-Retzius cells have to stop migrating,” says Dr. José Antonio del Río, group leader of the Molecular and Cellular Neurobiotechnology group at IBEC. “During the development of the nervous system, Sema3E can perform inhibition or attractive functions depending on the receptor that the target cells have. In this case, the Cajal-Retzius cells have only the PlexinD1 receptor, and by binding to the molecule Sema3E, cell migration is slowed.”
This paper represents the first demonstration of the functions of the signaling system Sema3E/PlexinD1 that is already known to have important implications in vascularization and cancer, during the neuronal migration process and the formation of the nervous system. The researchers demonstrated the action of system on Cajal-Retzius cells in mouse embryos, but more studies are still needed to see if this is a common process in other organisms, including humans. As a result, the IBEC group is collaborating with Vall d’Hebron Hospital in Barcelona to work together on future studies using their tissue bank.
Reference article: Ana Bribián, Sara Nocentini, Franc Llorens, Vanessa Gil, Erik Mire, Diego Reginensi, Yutaka Yoshida, Fanny Mann, José Antonio del Río (2014). Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex. Nat. Commun., 5, 4265
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