Neuronal migration is a powerful model to investigate how cellular behaviour is controlled at the genomic level.
The process of neuronal migration is complex but can be readily visualised and quantified and many of the genes involved have already been identified in fibroblasts and other simple cell culture models.
Our aim is to identify the transcriptional module that is activated in a newborn neuron to promote its migration and to determine how regulatory modules for migration differ in neurons that use different modes of migration (e.g. radial migration of cortical projection neurons, tangential migration of cortical interneurons, chain migration of adult-born olfactory interneurons).
We use in-utero electroporation and time-lapse video-microscopy of organotypic cortical slices to image neuronal migration and to study the regulation and function of candidate genes and identify the downstream pathways regulating this process.
In the publications listed below, we have identified the microcephaly gene Cenpj/Cpap as a transcriptional target of the proneural factor Ascl1 in progenitors and newborn neurons of the embryonic cerebral cortex.
We have shown that the Cenpj protein, which is associated with the centrosome, regulates the orientation of the mitotic spindle during progenitor division and is required to destabilise the microtubule cytoskeleton and to couple the nucleus with the centrosome during radial migration. Cenpj is therefore an essential component of the programme of neurogenesis activated by Ascl1, which regulates both progenitor divisions and neuronal migration (Garcez et al., 2015).
We have shown that Ascl1 also promotes the migration of cortical neurons by inducing the expression of the small GTP-binding protein Rnd3, and that an interaction of Rnd3 with the semaphoring receptor Plexin B2 fine-tunes the level of RhoA signaling in migrating neurons. Thus the convergence of a cell extrinsic Plexin pathway and a cell intrinsic proneural factor-small GTP-binding protein pathway determines the level of RhoA activity appropriate for neuronal migration (Azzarelli et al., 2014).
We have also found that the two proneural transcription factors co-expressed in cortical progenitors, Neurog2 and Ascl1, promote the migration of newborn neurons, each through induction of the expression of a different small GTP-binding protein, Rnd2 and Rnd3, respectively.
Neurog2 and Ascl1 have distinct roles in migration because they induce the expression of Rnd2 and Rnd3 at different times in the migration process and because Rnd2 and Rnd3 are located and regulate RhoA activity in different compartments of the migrating neurone. Therefore proneural factors regulate neuronal migration transcriptionally by directly controlling the spatio-temporal activity of the cytoskeleton regulator RhoA (Pacary et al., 2011)