Stroke Literature Synopses: Basic Science
There remains some plasticity even in adult brain, and after stroke, the brain tries to remodel damaged neuronal circuits. Neuronal precursor cells (NPCs) may participate in this process, but how NPCs move to lesion areas from subventricular zone (SVZ) remains to be fully understood. Three recent studies provide new fundamental mechanisms for neural migration in the central nervous system.
Itoh et al (Scratch regulates neuronal migration onset via an epithelial-mesenchymal transition-like mechanism. Nature Neurosci. 2013;16:416–425) proposed a novel mechanism for the conversion of neuroepithelial cells to migrating neurons or intermediate NPCs. During development, NPCs in the SVZ form a pseudostratified epithelial structure, and once they commit to becoming neurons (or intermediate NPCs), they delaminate and start migration. To reveal the underlying regulatory mechanisms, the authors focused on roles of Scratch1 and Scratch2, which are members of the Snail superfamily of transcription factors. They knocked down Scratch1 and Scratch2 in the neocortical NPCs during neocortical development by introducing constructs encoding corresponding short hairpin RNAs in utero. Knockdown of Scratch1 and Scratch2 showed a significant increase in the proportion of neocortical NPCs with their apical process attached to the ventricular surface. In turn, overexpression of Scratch1 or Scratch2 reduced the proportion, confirming that Scratch1 and Scratch2 are necessary for the initiation of NPC migration. Using in vitro and in vivo systems, the authors also showed that Scratch proteins induced the migration of NPCs without enhancing proliferation. Finally, to further elucidate the intracellular regulating mechanism of NPC migration, they examined the interaction between Scratch and an adhesion molecule E-cadherin because E-cadherin is one of the most important targets of the Snail superfamily. By manipulating expressions of E-cadherin or Scratch1 in utero, the authors have demonstrated that Scratch1 is an important trigger for neuronal migration from SVZ through, at least in part, downregulation of E-cadherin in the developing neocortex.
Because most neurons are generated at different brain region from their destination, they need to move to their final location once they depart from the point of departure. However, little is known about the intracellular molecular mechanisms controlling NPC migration. Sonego et al (Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal brain. J Neurosci. 2013;33:12171–12185) examined the mechanisms by which the actin-bundling protein fascin regulates neuroblastoma migration. During development, neuroblasts in the SVZ migrate along the rostral migratory stream to become interneurons in the olfactory bulb. The authors showed that fascin protein is highly upregulated in SVZ-derived migratory neuroblasts, and Fascin-1ko mice displayed an abnormal rostral migratory stream and a smaller olfactory bulb. In addition, fascin depletion altered the polarized morphology of migrating neuroblasts and significantly impaired neuroblast migration without affecting cell proliferation. To identify the mechanisms of fascin-related neuroblast migration, the authors showed that (1) fascin phosphorylation on Serine 39 by protein kinase C regulated this process, and (2) cannabinoid signaling played an essential role in the fascin–protein kinase C interaction of migrating cells. Because disrupting migration affects neuronal maturation, these results suggest that a tight regulation of fascin phosphorylation by extracellular cannabinoid signal contributes to efficient neurogenesis in the developing brain.
As noted, cell polarity is a key factor for cell migration. Wang et al (Transmembrane protein MIG-13 links the Wnt signaling and Hox genes to the cell polarity in neuronal migration. Proc Natl Acad Sci USA. 2013;110:11175–11180) showed that MIG-13 regulated the asymmetrical distribution of the actin cytoskeleton in the leading migratory edge. MIG-13 is an evolutionarily conserved transmembrane protein, and the authors used Caenorhabditis elegans (C elegans) to examine whether MIG-13 plays autonomous roles in the migration of Q neuroblasts. Q neuroblasts in C elegans are bilaterally symmetrical cells on the left and right. Wnt pathway activates homeobox gene mab-5 to promote the posterior migration of Q neuroblasts on the left and its descendants (QL.x). In turn, another homeobox gene lin-39 accelerates the anterior migration of Q neuroblasts on the right and its descendants (QR.x). To examine the regulatory targets of MAB-5 and LIN-39, the authors prepared transgenic C elegans lines, and using live fluorescence imaging techniques, this study showed that (1) LIN-39 increased the expression of mig-13 in QR.x for the anterior migration, and (2) Wnt signaling and MAB-5 inhibited the expressions of lin-39 and mig-13 for the posterior migration. Taken together, these data revealed the autonomous function of mig-13, a worm homolog of mouse low-density lipoprotein receptor–related protein 12, in neural migration.
These 3 studies have demonstrated the novel mechanisms of neural migration during development. But after stroke, the process of neurogenesis (ie, neuroremodeling) may take similar steps as seen in the developmental stages. Hence, uncovering the basic molecular players involved in neural migration will help us to exploit the therapeutic approach of promoting neuronal repair after brain injury.
- © 2013 American Heart Association, Inc.