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Newly generated neuroblasts from the subventricular zone of the adult brain migrate as neuronal chains within a network of astroglial tubes in the rostral migratory stream. This highly directed, rapid migration channels new neurons to the olfactory bulb. In this issue of Neuron, Kaneko et al. demonstrate that migrating neurons dynamically remodel the morphology and organization of astroglial tubes to promote long distance, directional migration of neurons in the adult brain.
Reciprocal interactions between migrating neurons and astroglia play influential roles in the guidance and placement of newly generated neurons in the cerebral cortex. During embryonic development, migrating neurons modulate the function of radial glial cells as neuronal migratory guides in the neocortex (Hatten, 1985; Rakic, 2003). In contrast, in the adult brain, long distance neuronal migration is thought to occur in a glial-independent manner. In the rostral migratory stream (RMS), newly generated neurons from the subventricular zone migrate along each other as oriented chains toward their target locations in the olfactory bulb (Wichterle et al., 1997). During this process, neurons are encapsulated by a complex network of astrocyte tubes (Doetsch and Alvarez-Buylla, 1996; Lois et al., 1996). The functional significance of these astroglial tubes, whether they merely act as barriers to prevent the dispersion of the young neuroblasts into the surrounding tissue or if they actively guide or orient the new neurons, has remained unclear.
In this issue of Neuron, Kaneko et al. (2010) provide evidence that new neurons may actively modulate the formation and organization of the astrocyte tunnel network to facilitate their directed migration in the mature brain. To explore the impact of neuron-astroglial interactions in directional migration in the adult brain, they analyzed neuronal migration and RMS organization defects in Slit1 null mice. Previous findings demonstrated that Slit1, a diffusible chemorepulsive protein, is expressed by migrating neurons in the RMS and may cell autonomously regulate their migration (Nguyen-Ba-Charvet et al., 2004). Kaneko et al. (2010) extend these findings by live-imaging the migration of Slit1 deficient neurons in brain slices and by mapping the migratory behavior of wild-type (wt) and Slit1−/− neurons transplanted into either wt or Slit1−/− RMS. These studies clearly establish that both cell-autonomous and non-cell-autonomous effects of neuronal Slit1 are critical for oriented neuronal migration in the RMS. Importantly, they noticed that the astrocyte tube network is significantly disrupted in Slit1−/− RMS. Astrocyte processes, instead of orienting parallel to and surrounding the migrating neuroblast chains, were found to invade and run across the chains of migrating neurons in the absence of Slit1. This observation suggested that neuronal Slit1 may modulate the organization of the astrocyte tubes in the RMS to promote oriented neuronal migration and that disruption of this process in the Slit1−/− RMS may be an underlying cause of the migratory defect. To test this, they examined the patterns of neuron-astroglial interactions in vitro in the absence of neuronal Slit1. Slit1−/− neurons made irregular associations with astroglia, resulting in altered migration. Slit1 repelled astrocytes in vitro without affecting their survival or proliferation. How this chemorepellent activity of Slit1 is counterbalanced or modified during neuron-astroglial interactions in vivo is unclear. However, neuron or astrocytespecific Slit receptor perturbance assays indicate that the neuronal Slit1 effect is in part mediated by Slit's receptors, Robo2 and 3, expressed in astrocytes. Slit1-dependent, Robo receptor signaling in the RMS astrocytes promoted neuronal migration on astrocytes in vitro and induced changes in astrocyte morphology (i.e., furrow-like membrane invaginations) that may accommodate chains of migrating neurons. Together, these results support their compelling hypothesis that new neuroblasts in the postnatal brain dynamically modulate the astroglial tunnel network along their migratory route to promote their directional migration.
Although this study utilizes several elegant in vitro neuron-astroglial assays and cell-type-specific manipulation of the Slit-Robo signaling system to demonstrate the influential role of new neurons in modifying the astroglial network, further in vivo evidence from postnatal neuronal or astroglial-specific conditional inactivation of Slit1, Robo2, and Robo3 will be essential to firmly establish the in vivo relevance of this mode of neuron-glial interactions in adult neuronal migration. The expression of Robo receptors in both neurons and astrocytes and the known influence of nonneuronal Slit on neuronal migration in the RMS (Sawamoto et al., 2006) support the need for such studies.
The identification of astroglial membrane furrows as a significant indicator of neurons' ability to modify their migratory route highlights several interesting issues regarding their role in neuronal migration in adult brain. Membrane deformations of neurons have been shown to be essential for their normal migration (Guerrier et al., 2009). The chemorepellent-like activities of neuronal Slit1 that changed the membrane contours of the surrounding astroglial cells, shown in this study, suggest that co-coordinated membrane deformation of both migrating neurons and the surrounding astroglial cellular environment are critical to promote oriented neuronal migration. Whether the Slit-Robo signaling system is such a coordinator in the RMS remains to be determined. Further, the membrane furrows that are induced by migrating neurons could be simple mechanical deformations or sites of accumulation of specific signaling or adhesion complexes. Do attractive signals between astrocytes and migrating neurons also lead to the formation of similar furrows? Do these furrows provide any directional orientation cues to migrating neural chains? Do they only modulate neuronal migration or may they also provide contact-mediated signals to trigger the mitosis of immature neuroblasts in the RMS? (Lim and Alvarez-Buylla, 1999; Menezes et al., 1995). Do new neurons induce furrow formation and organizational changes in RMS astrocytes only and not in astroglia from elsewhere in the brain parenchyma? Further ultrastructural as well as molecular characterization of these astroglial furrows will be informative in deciphering their importance in the RMS.
New neurons, in addition to clearing the impeding astrocyte processes away from the path of migrating neuronal chains and modifying the contours of the astroglial tube membrane surfaces to fit these moving chains, may also dynamically modulate the overall astrocyte tube network (Figure S4 of Kaneko et al.). It is attractive to speculate that this ability to constantly modify the organization of the tubular network of astrocytes may help to seamlessly channel the streaming chains of new neurons toward the olfactory bulb in an efficient manner, without creating choke points along the way. Recent studies have also identified blood vessels within the RMS as additional scaffolds for chain migration of neurons (Snapyan et al., 2009; Whitman et al., 2009). Astroglial cells form intimate associations with these blood vessels and neuron-astroglial interactions actively modulate the ability of the vasculature to influence neuroblast migration (Snapyan et al., 2009). In this context, it will be important to understand the impact of astroglial tube remodeling on RMS vasculature and its effects on neuroblast chain migration. Such interactions might occur via Slit1-independent mechanisms since the Slit1−/− RMS vasculature appears to be unaffected (Figure S1 of Kaneko et al.).
The idea that new neurons generated in the mature brain can facilitate their own migration through the complex brain parenchyma to their proper target areas by modifying their migratory highway to suit their directional movement has potentially significant implications. Although the existence of rostral migratory stream-like long distance migration in the adult human brain remains controversial (Curtis et al., 2007; Sanai et al., 2007), the ability to modify the migratory route to facilitate the targeted movement of endogenously generated or transplanted neuroblasts will have a significant impact on regenerative therapeutic approaches aimed at promoting functional recovery after brain injuries. Effective functional repair strategies in the adult brain depend not only on replacement with appropriate numbers and types of neurons, but also on proper migration of transplanted or endogenously generated neurons to sites where they are needed. Further characterization of the mechanisms underlying new neurons' ability to modify their migratory route with the help of astroglial cells in the mature brain will help optimize these strategies.