The molecular determinants of brain connectivity
Neuronal connections form during development and are driven by the coordination of cell migration, axon guidance and synapse formation. Research studies over the years have identified molecular cues that are essential in these processes, but the signalling mechanisms have yet to be elucidated. The scope of the EU-funded NEUROMIGRATION (Novel molecular mechanisms of neuron migration in the developing cortex and their contribution to related diseases) project was to assess the role of a family of leucine-rich transmembrane proteins (LRTPs) – the fibronectin and leucine-rich transmembrane proteins (FLRT1-FLRT3) – during nervous system development in vivo. Previous work had underscored a role for FLRT2 in regulating the migration of the basal progenitor (BP) cells – the cells that give rise to the differentiating neurons in the brain cortex. Researchers observed that two of the best-studied axon guidance molecules, Netrin-1 and Slit1, cooperated during development to connect the thalamus with the cortex for processing sensory information. This connection was reinforced through the interaction of FLRTs with the receptors of these two molecules. In addition, a cooperation of FLRT2 and FLRT3 was necessary for maintaining the interneuron migratory streams. The routes of neuronal migration in the brain cortex avoided FLRT-expressing territories suggesting that FLRTs might act as repulsive cues. Deletion of FLRT2 and FLRT3 in the whole nervous system of the mouse affected only specific interneuron migration. This indicates that the defect would lie in the distribution of interneurons once they reach the cortex. Further analysis into the molecular interplay of FLRTs in the developing brain unveiled a novel interaction with the Rho GTPase Rnd3. Taken together, the results of the NEUROMIGRATION study identified FLRTs as important multi-task players that control different processes and possess different mechanisms of action, depending on the cellular context. These important regulators of nervous system development could further serve as potential therapeutic targets for neurological diseases.
Keywords
Brain, nervous system, development, migration, LRTP, FLRT, Rnd3
