Motility is a universal property of newly generated neurons. How cell migration is coordinately regulated with other aspects of neuron production is not well understood. Here we show that the proneural protein neurogenin 2 (Neurog2), which controls neurogenesis in the embryonic cerebral cortex, directly induces the expression of the small GTP-binding protein Rnd2 (ref. 3) in newly generated mouse cortical neurons before they initiate migration. Rnd2 silencing leads to a defect in radial migration of cortical neurons similar to that observed when the Neurog2 gene is deleted. Remarkably, restoring Rnd2 expression in Neurog2-mutant neurons is sufficient to rescue their ability to migrate. Our results identify Rnd2 as a novel essential regulator of neuronal migration in the cerebral cortex and demonstrate that Rnd2 is a major effector of Neurog2 function in the promotion of migration. Thus, a proneural protein controls the complex cellular behaviour of cell migration through a remarkably direct pathway involving the transcriptional activation of a small GTP-binding protein.

Projection neurons destined for the cortical plate are generated sequentially from the proliferative ventricular and subventricular zones (VZ/SVZ) of the pallium. However, the respective contribution of both proliferative zones to the generation of cortical plate neurons is better established in humans and non-human primates than in rodents. We identified Cux2 as a new marker for murine cortical subpopulations and used it to provide new insights to the development of the mouse cortex. Cux2 is an orthologue of the Drosophila cut gene, which encodes a homeodomain protein involved in neuronal specification. During cortical development Cux2 identifies two subpopulations with different spatial origins, migratory behaviours and phenotypic characteristics: (i) a population of interneurons, which invades the pallium from the subpallium; and (ii) a neuronal population produced in the pallium around embryonic day 11.5, which divides in the SVZ and accumulates in the intermediate zone (IZ). Subsequently, Cux2 is a marker of upper cortical layers. Using different molecular markers and Pax6-deficient mice, we provide data that suggest a relationship between the early-determined Cux2-positive neuronal precursors in the SVZ/IZ and upper layer neurons. This suggests that laminar determination of upper cortical layer neurons occurs during the earliest stages of corticogenesis.

The generation of a functional nervous system involves a multitude of steps that are controlled by just a few families of extracellular signaling molecules. Among these, the fibroblast growth factor (FGF) family is particularly prominent for the remarkable diversity of its functions. FGFs are best known for their roles in the early steps of patterning of the neural primordium and proliferation of neural progenitors. However, other equally important functions have emerged more recently, including in the later steps of neuronal migration, axon navigation, and synaptogenesis. We review here these diverse functions and discuss the mechanisms that account for this unusual range of activities. FGFs are essential components of most protocols devised to generate therapeutically important neuronal populations in vitro or to stimulate neuronal repair in vivo. How FGFs promote the development of the nervous system and maintain its integrity will thus remain an important focus of research in the future.

We showed previously that the proneural genes Neurogenin1 (Ngn1) and Ngn2 are required to specify the phenotypes of early- and not late-born neurons in the neocortex, acting in part through repression of Mash1, a third cortically expressed proneural gene. The precise timing of Ngn1/2 specification activity was unexpected given these genes are expressed throughout cortical development, prompting us to search for a later function. Here we reveal that Ngn2 and Mash1 are expressed in a dynamic fashion, acquiring a cell cycle-biased, nonoverlapping distribution, with preferential expression in prospective basal progenitors, during mid corticogenesis. We also identified a new function for Ngn2 during this latter period, demonstrating that it is required to regulate the transit of cortical progenitors from the ventricular zone (VZ) to the subventricular zone. Notably, Ngn2 regulates progenitor maturation at least in part through repression of Mash1 as misexpression of Mash1 strongly enhanced progenitor cell exit from the VZ. Significantly, the ability of Mash1 to promote progenitor cell maturation occurred independently of its ability to respecify cortical cells and is thus a novel function for Mash1. Taken together, these data support a model whereby Ngn2 and Mash1 function together to regulate the zonal distribution of progenitors in the developing neocortex.

The morphogen Sonic Hedgehog (Shh) controls the generation of oligodendrocyte (OLs) during embryonic development and regulates OL production in adulthood in the cortex and corpus callosum. The roles of Shh in CNS repair following lesions associated with demyelinating diseases are still unresolved. Here, we address this issue by using a model of focal demyelination induced by lysolecithin in the corpus callosum of adult mice. Shh transcripts and protein were not detected in control animals but were upregulated in a timedependent manner in the oligodendroglial lineage within the lesion. We report an increased transcription of Shh target genes suggesting a broad reactivation of the Shh pathway. We show that the adenovirus-mediated transfer of Shh into the lesioned brain results in the attenuation of the lesion extent with the increase of OL progenitor cells (OPCs) and mature myelinating OL numbers due to survival, proliferation, and differentiation activities as well as the decrease of astrogliosis and macrophage infiltration. Furthermore, the blocking of Shh signaling during the lesion, using its physiological antagonist, Hedgehog interacting protein, results in a decrease of OPC proliferation and differentiation, preventing repair. Together, our findings identify Shh as a necessary factor playing a positive role during demyelination and indicate that its signaling activation stands as a potential therapeutic approach for myelin diseases.