| Popis: |
During the development of the cerebral cortex, newborn neurons migrate radially from the ventricular/subventricular zones of the dorsal telencephalon to reach the above cortical plate, where they acquire laminar-specific characteristics and establish appropriate neuronal connections. Recent works from our laboratory have shown that two proneural factors operating in the embryonic cortex, Neurog2 and Ascl1, control radial migration of cortical neurons through the transcriptional regulation of two small GTP binding proteins, Rnd2 and Rnd3. These studies have shed light onto the genetic programs that regulate neuronal migration in the wider context of cortical development. However, the molecular mechanisms that mediate the pro-migratory activity of Rnd proteins are not yet completely understood. Several studies in non-neuronal cell types have suggested a potential role for the related GTPase RhoA, a major modulator of cell cytoskeleton. Here, we used a series of in vivo genetic interaction and rescue experiments to demonstrate that Rnds stimulate neuronal migration by inhibiting RhoA signalling, a mechanism that, in the case of Rnd3, involves the regulation of a RhoA inhibitor, p190RhoGAP. In addition, we undertook a candidate approach to identify other potential Rnd partners in the control of radial migration. Interestingly, a class of transmembrane receptors that belong to the plexin family of axon guidance molecules was previously shown to functionally interact with Rnd proteins. Here, we found that a member of the PlexinB subfamily, PlexinB2, interacts with Rnd3 and regulates the morphology and the migration of cortical neurons. Moreover, our in vivo genetic interaction studies and our molecular Fluorescence resonance energy transfer (FRET) data indicate that PlexinB2 and Rnd3 are responsible for fine-tuning the levels of RhoA activation in migrating neurons. Through a better characterization of the molecular mechanisms that control neuronal migration, this work will contribute to the understanding of the aetiopathology of several human brain disorders that are associated with neuronal migration defects. |
