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Brazilian Journal of Medical and Biological Research (2002) 35: 1411-1421 Migration in the 1411 ISSN 0100-879X

Cell migration in the postnatal subventricular zone

J.R.L. Menezes1, M. Marins1, 1Laboratório de Neuroanatomia Celular, Departamento de Anatomia, J.A.J. Alves1, M.M. Fróes1 Instituto de Ciências Biomédicas, and 2Instituto de Biofísica Carlos Chagas Filho, and C. Hedin-Pereira2 Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil

Abstract

Correspondence New neurons are constantly added to the of rodents Key words J.R.L. Menezes from birth to adulthood. This accretion is not only dependent on · Postnatal Departamento de Anatomia sustained neurogenesis, but also on the migration of and · Chain migration ICB, CCS, Bloco F, UFRJ immature neurons from the cortical and striatal subventricular zone · Rostral migratory stream 21941-590 Rio de Janeiro, RJ (SVZ) to the olfactory bulb. Migration along this long tangential · Brasil pathway, known as the rostral migratory stream (RMS), is in many · Gap junctions Fax: +55-21-290-0587 ways opposite to the classical radial migration of immature neurons: · Radial glia E-mail: [email protected] it is faster, spans a longer distance, does not require radial glial Presented at the IV International guidance, and is not limited to postmitotic neurons. In recent years UNESCO Course on “What the many molecules have been found to be expressed specifically in this Developing Cerebral Cortex Tells pathway and to directly affect this migration. Soluble factors with About the Adult Cortex (and Vice inhibitory, attractive and inductive roles in migration have been Versa)”, Rio de Janeiro, RJ, Brazil, described, as well as molecules mediating cell-to-cell and cell-sub- December 3-7, 2001. strate interactions. However, it is still unclear how the various mol-

Research supported by CNPq, TWAS, ecules and cells interact to account for the special migratory behavior FUJB, and FAPERJ. in the RMS. Here we will propose some candidate mechanisms for roles in initiating and stopping SVZ/RMS migration.

Received July 12, 2002 Accepted September 17, 2002 Introduction the most extensively studied. In this case, transient glial cells, the radial glia, form a is an imperative require- palisade that courses along the cerebral wall ment during development of most CNS re- from the ventricular zone to the pial surface gions. Newly generated neurons must leave serving as a scaffold for the migration of the germinal layers and move, sometimes a young neurons (1). This form of migration is great distance, to reach their final destina- usually referred to as radial migration, al- tion. This migratory behavior can be classi- though alternative types of radial cell move- fied as radial or tangential depending on the ment, independent of radial glia, have been orientation of the cell movement in relation described (4,5). Neuronophilic migration is to the pial surface (1). Alternatively, migra- a less well-studied migratory behavior in tion can be viewed as gliophilic, neurono- which new neurons are associated with axons philic, and homophilic in relation to the cell instead of glial processes during migration substrates of migration (1-3). The glia-de- (1,2). This mode of migration can assume pendent radial migration of immature neu- various orientations, such as the tangential rons, ubiquitous in the embryonic CNS, is movement of precur-

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sors en route to the cerebral cortex in which tion and proliferation (11), as well as a pre- corticofugal axons appear to function as their cocious biochemical differentiation (11). substrate (6). Finally, homophilic migration Recently, there has been a resurgence of was thus termed because in this modality, interest in the SVZ, both in the neonatal and migrating cells, neurons and neuroblasts, use adult , where this system has been used each other as substrate, forming long chains in studies ranging from cell migration to of cells in situ and in vitro (3,7). This form of biology. migration was first described for the cells In brief, new neurons derived from the that leave the anterior subventricular zone SVZ migrate long distances, invade the ma- (SVZ) towards the olfactory bulb (Figure 1) ture nervous tissue and establish new func- and form the rostral migratory stream (RMS; tional circuits with the existing neurons (12). 8). This tangential migratory movement of This is exactly the behavior one would wish neurons and neuroblasts is directly associ- from a source of new neurons that could be ated with the neurogenesis of olfactory bulb used to substitute neuron depletion. The un- that occurs postnatally in the derstanding of the mechanisms by which SVZ- SVZ, a highly proliferative layer in the early derived cells migrate may be then as important postnatal that persists well into adult- as understanding how this region sustains con- hood (7-10). tinued neurogenesis throughout adulthood. Besides the unusual mode of migration, Here we will review the special characteris- cells within the SVZ/RMS display other un- tics of this tangential migration and the cel- usual features, such as simultaneous migra- lular interactions that drive this behavior.

Figure 1. Summary of subven- tricular zone/rostral migratory stream (SVZ/RMS) tangential mi- gration towards the olfactory bulb (OB) in a parasagittal representa- tion of the anterior forebrain in Progenitors or immature neuron the early postnatal animal. Migra- tion in the RMS can be divided Mitosis Periglomerular cell into three overlapping phases that correspond roughly to differ- Granular cell ent portions of the pathway (num- Radial glia Cx cc bers in circles). 1) Initially cells go through a phase in which they lv migrate but are still able to divide. Radially migrating neuron That happens mostly in regions 1 of the SVZ close to the where mitosis is more frequent. 2) At a given moment, AOB St already within the RMS, cells defi- 3 nitely abandon the cell cycle and continue migration towards the OB. 3) Upon reaching the OB, cells switch from tangential to ra- dial migration and invade the OB 2 MOB parenchyma, turning on their dif- Tu ferentiation into granular and periglomerular cells. In early post- natal life radial glia form a scaffold for this pathway as represented with a few examples (more details can be obtained in Ref. 16). Radial glia in the OB were omitted for simplicity. Although only the early postnatal period is represented in this figure, migration in the adult SVZ/RMS appears to obey similar phases and pattern. Note also that, although not represented, chain migration can also occur from more caudal regions. The SVZ/RMS is represented in stipples. AOB, accessory olfactory bulb; Cx, cerebral cortex; cc, corpus callosum; lv, lateral ventricle; MOB, main olfactory bulb; St, ; Tu, olfactory tubercle.

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Cellular composition of the SVZ (14). Additional evidence for this comes postnatal SVZ from infusion of truncated ephrins that by disturbing proliferation cause the appearance The SVZ is not a homogeneous and of large islands of proliferating cells (22). The stable region throughout the life of an ani- relevance of these discrete compartments is mal. The cellular composition of young and still not fully understood. They may reflect the adult SVZ differs little except for relative segregated distribution of specific cells and/or numbers, with both containing immature neu- growth factors with proliferation-inducing ca- rons, neuroblasts, undifferentiated precur- pacities. Alternatively, they may arise from the sor cells, astrocytes and (13,14). A preferential adhesion between homophilic main difference is that in the young SVZ the migrating cells, thus excluding proliferating major glial component is the radial glia, cells from the migratory chains. absent in the adult (15,16). The astrocytes of the adult SVZ/RMS surround the migrating Tangential migration within the cells providing an astrocytic scaffold to the SVZ/RMS SVZ that forms long cylinders denominated glial tubes (7,17). Recently, we have demon- The migration of neuroblasts and young strated that such a scaffold does in fact exist neurons generated in the SVZ can also be in the young SVZ formed by the cell bodies divided into three phases, independent of the and processes of transforming radial glia age of the animal (Figure 1). Based on the (17). decreasing caudal-to-rostral proliferative gra- dient of the RMS (8,19,23,24) we can infer Compartments in the postnatal SVZ that cells go through a phase switch, in which first migration and proliferation can occur Proliferation in the SVZ was thought to simultaneously, to another, when migrating occur homogeneously, in contrast to, for cells do not reenter the cell cycle. The exact example, the embryonic ventricular zone, time and place where this transition occurs where a characteristic nuclear movement are yet to be determined, although this must segregates cells in different stages of the cell happen somewhere along the RMS. This cycle (18). Recently, we have demonstrated transition appears to become more spatially that the S-phase cells in the young SVZ/ restricted with age, when cell division is RMS are preferentially concentrated in the mostly restricted to the region overlying the periphery of the SVZ/RMS tube-like struc- lateral ventricles. The third phase occurs ture spatially segregated from migratory cells within the bulb, where the cells go through (19). A similar periphery-to-core pattern of another phase switch, this time from a tan- distribution was recently described for the gential to a radial migratory mode (10,23). It expression of zebrin II (20), which rein- is possible that the glial cells in the olfactory forces the idea that the early postnatal SVZ is bulb provide the necessary signals for the organized in discrete cellular compartments. orientation switch of these migrating SVZ/ In addition, we have described a discrete RMS-derived cells. In support for this view spatial pattern of -mediated cell we have shown that the radial glia of the coupling involving neuroblasts and radial olfactory bulb are different, at least morpho- glia that closely resembles the S-phase dis- logically, from those of the cerebral cortex tribution in the young SVZ (21). It is pos- (17). However, radial glia are not present in sible that some compartmentalization per- the adult olfactory bulb, and therefore other sists to adulthood since discrete islands of sources for positional signaling have to be proliferative cells are also found in the mature postulated.

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Cellular substrates for migration may be the source of a secreted protein with a migration-inducing activity (MIA) (26). In Evidence converges to support the idea contrast, it is possible that the interaction that migration within the RMS is glia inde- with glial cells may reduce migratory speed, pendent. Most important for this conclusion which could account for the much lower was the demonstration that SVZ/RMS cells speeds, 30 to 50 µm/h, for in situ migration can migrate in culture without the presence within the RMS (7,10) or in SVZ explant of glial cells (3). In addition, in the young cultures rich in glia (26) when compared to SVZ/RMS, migration is orthogonal to the cultures with Matrigel which are poor in radial glial palisade (16) and because of this glia, and migration reaches speeds well over arrangement RMS cell migration has been 100 µm/h (3). described as glia independent (10,16). How- ever, a glial sheath encircles migrating cells Push, pull and roll: molecular both in young and adult (7,15,17). substrates for migration Until now it has not been elucidated if these scaffolds have any function in guiding SVZ/ Despite the growing interest in the RMS migration. Apparently, astrocytes of mechanisms underlying migration in the the SVZ have the ability of inducing neuro- RMS, the factors that control this phenome- blast proliferation through a cell-to-cell con- non remain largely unknown. Several mol- tact mechanism (25). In addition, ensheath- ecules have already been shown to regulate

Figure 2. Summary scheme of ing astrocytes and possibly radial glial cells this type of migration (Figure 2), but we are confirmed and putative mol- ecules governing cell migration in the subventricular zone/rostral migratory stream (SVZ/RMS) from birth to adulthood. Influ- Cell-cell Matrix proteins Soluble factors/ ences of diffusible factors, cell- receptors Gap junctions cell and cell-substrate interac- DCC tions on migration are illustrated. /Tenascin/ Only neuroblasts (NB), astrocytes Eph and ephrins Robo CSPGs (A) and radial glia (RG) are repre- Growth factors sented. To simplify the scheme 9-O-ac ganglioside RG and A were considered PSA-NCAM MIA equivalent (RG/A). Presently, we Netrin can identify many different fac- Cadherins tors involved in directed chain mi- Slit gration to the olfactory bulb (OB) through the RMS. Illustrated are known soluble factors, mem- brane-bound and extracellular RG/A molecules that affect this migra- OB A tion, and their confirmed cellular and tissue location (in black). Mol- ecules in light gray represent pos- sible but not demonstrated inter- NB actions of these molecules. Al- though most molecules repre- sented have been shown to be directly involved in RMS migra- tion, little is known about how NB they interact with each other. See text for details. CSPGs, chon- droitin sulfate proteoglycans; DCC, deleted in colorectal cancer Septum receptor; MIA, migration-induc- ing activity.

Braz J Med Biol Res 35(12) 2002 Migration in the subventricular zone 1415 far from a working model comparable to the cells to end up in the septum (26). Regard- one proposed for radial migration (27). Simi- less of whether its main effect is inhibitory lar to radial migration one would expect to or repulsive, Slit alone is not sufficient to find attractant, repulsive, and permissive account for the directed migration to the molecules, as well as initialization and stop olfactory bulb. It does not explain, for ex- signals. ample, why cells do not abandon the RMS to invade adjacent tissue, such as the cortical Soluble factors white matter or the striatum. A frequent assumption is that the astrocytic sheath or Attractants. Judging from the stereotypi- alternatively the radial glial sheath acts as a cally olfactory bulb-directed migration, a barrier for this outflow (33). However, this is powerful attractant gradient originating in yet to be verified. the olfactory bulb could be postulated; how- Growth factors. Several growth factors ever, unidirectional migration was still de- have been shown to promote proliferation of tected in the absence of the olfactory bulb the SVZ population, such as EGF, FGF (34, (28). Sensory deprivation also did not affect 35), TGF-ß (36) and BDNF (37,38). Albeit cell migration in the RMS although it did no direct effect on cell migration has been alter the number of surviving interneurons demonstrated, intrathecal and intraventricu- (24,29). It was only recently that a putative lar infusion of growth factors increased the attractant from the olfactory bulb was pro- numbers of cells moving down the SVZ/ posed. Murase and Horwitz (30) demon- RMS pathway (34,35,37,38), as well as the strated an effect of a netrin or netrin-like number of cells straying from the SVZ and molecule mediated by the receptor deleted in invading neighboring tissue (35,37). These colorectal cancer (DCC) in the guidance of results may be due solely to the increase in migrating cells within the RMS. cell number; however, a role of specific Repellents and inhibitors. The secreted growth factors augmenting SVZ/RMS cell proteins, Slit1 and 2, were the only mol- migration cannot as yet be discarded. ecules described so far that could influence the migration direction of RMS cells via a Cell contact-mediating molecules repulsion-mediated mechanism (31). These molecules are expressed in the septum and Few molecules that mediate cell-to-cell choroid plexus, regions that could be impor- interactions have been implicated in tangen- tant in driving RMS cells rostrally in the tial cell migration within the SVZ/RMS. To olfactory bulb direction (32). In mammals, date these are the polysialylated form of Slit was first described to serve as an axonal NCAM (PSA-NCAM; 39,40), ganglioside guidance signal that impedes commissural 9-O-acetylated GD3 (9-O-acGD3; 41-43), axon recrossing, in association with its re- ephrins and eph receptors (22), and connex- ceptor Robo present in the commissural axons ins (21,44). Despite their very diverse na- (32). These molecules also appear to have a ture, perturbing any of these molecules greatly role in directing tangential migration from reduces or stops migration of SVZ cells. the ganglionic eminence, so that the migrat- This indicates that many different intracellu- ing cells avoid entering the Slit expressing lar signaling pathways converge to elicit this striatal primordium in their pathway towards behavior. the cerebral cortex (32). Recent evidence PSA-NCAM was the first molecule to be suggested that, rather than having a repul- implicated in chain migration in the SVZ/ sive action, Slit could be inhibitory for SVZ/ RMS (10). Already in the late eighties PSA- RMS cells, reducing the chance of RMS NCAM was immunodetected in the SVZ and

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its role in olfactory bulb postnatal neurogen- sible for ephrin-B, which was specifically esis was postulated (45). Migrating and pro- located to astrocytes (22). Infusion of clus- liferating cells of the SVZ typically express tered soluble EphB2 and ephrin-B2 disrupted the polysialylated form of NCAM (10,46). chain migration in the SVZ/RMS. However, The genetic deletion of the embryonic NCAM this result may be due to a direct effect on (180 kDa; 9,40,46), as well as enzymatic proliferation (22) removal of polysialic acid (PSA; 39,40) It may not be surprising that ganglioside greatly reduces or abolishes SVZ/RMS cell 9-O-acGD3 is involved in RMS cell migra- migration. However, given the molecular tion since it is expressed in a spatiotempo- nature of PSA-NCAM, it is difficult to un- rally regulated manner in regions in which derstand how this molecule could mediate cell migration and process outgrowth occur homophilic interactions, since the PSA moi- in the developing CNS and peripheral ner- eties would, if anything, impede cell adhe- vous system (48). This glycolipid has been sion (39,40). It can be reasoned that PSA- directly implicated in external granule cell NCAM favors migration by acting as a nega- radial migration in the cerebellum (48,49). tive regulator for cell-cell interaction, pre- Initially it was thought to mediate only venting cells from interacting too tightly. gliophilic migration via a homophilic inter- Indeed, NCAM knockout mice in which all action of this ganglioside on the surface of isoforms were deleted revealed a speed re- migrating neuronal precursors and radial glial duction but not abolition of chain migration cells (48). However, 9-O-acGD3 molecules of SVZ/RMS cells (46). Therefore, due to were also shown to be expressed in the de- these results and the nature of the PSA- veloping and adult SVZ/RMS labeling mi- NCAM homophilic interaction, it could be gratory profiles (41). Their role as possible expected that other molecules would partici- mediators of neuroblast homophilic migra- pate in the migration of SVZ cells. tion was confirmed in studies in which gan- Eph receptors and their ligands ephrins glioside 9-O-acGD3 was shown to be pres- were shown to be directly involved in regu- ent in migrating chains of cells devoid of glia lating migration and proliferation in the post- in postnatal SVZ explant cultures (42). Im- natal SVZ (22). This family of receptor ty- munoblocking ganglioside 9-O-acGD3 pro- rosine kinase and their ligands mediate bidi- duced a drastic decrease in the migration rectional signaling between cells and were halo in these explants (43). One could specu- shown to be implicated in a variety of devel- late that PSA-NCAM and 9-O-acGD3 would opmental events (47). In general, ephrin and be expressed in different subsets of the SVZ eph receptor interaction lead to contact-de- cells but in general both molecules are found pendent cell repulsion involved in guiding in the same cells (42). Recent evidence sug- axons and migrating cells (47). This repul- gests that these gangliosides might reside in sion effect may also play a part in boundary focal adhesion sites together with integrins formation restricting cell intermingling and and other adhesion-mediating molecules per- communication (47). Nevertheless, ephrin forming a still obscure role. Arising possi- and eph receptor activation can trigger intra- bilities for the function of this molecule cellular signaling and the outcome may not range from its providing a calcium-rich mi- be just repulsive, since, for example, eph croenvironment on the cell surface to its receptor activation may lead to an increase direct interaction with other surface mol- in the expression of cell adhesion molecules ecules and extracellular matrix (48). Recent (47). Expression of EphB1-3, EphA4 and studies have shown that the GD3 ganglio- ephrins-B2/3 was detected in the SVZ/RMS, side functions as a receptor for tenascin-R although cellular localization was only pos- and -C leading to the regulation of intracellu-

Braz J Med Biol Res 35(12) 2002 Migration in the subventricular zone 1417 lar phosphorylation of focal adhesion ki- may be a key component for the initiation of nases (50). It is possible that the acetylation migration, in contrast to the radial migration of this molecule could regulate its interac- in the embryonic cortex, where uncoupling tion with the extracellular matrix during cell is a possible start signal for migration (52). migration and axon extension. Extracellular matrix molecules. From Recently gap junction intercellular com- birth to adulthood the SVZ/RMS pathway munication (GJIC) has been implicated in provides a diverse extracellular environment the regulation of SVZ cell migration, based to migrating cells, in which some molecules on connexin 43 expression (51), ultrastruc- are specifically enriched, such as tenascin- tural localization of gap junctions (15) and C, proteoglycans (33,56), and laminins (30). the presence of dye coupling (21) within the Extracellular matrix molecules can be seen SVZ/RMS. Cell coupling partners within the as providing an instructive and/or permis- SVZ/RMS have not yet been determined, sive environment, important for tangential but dye coupling studies indicate that homo- cell migration, in a similar fashion as seen cellular and heterocellular cell coupling is for neuronal radial migration (27). present, involving both glial cells and neuro- Extracellular molecules involved in blasts (44 and Marins M, Fróes MM and boundary formation such as tenascin-C and Menezes JRL, unpublished observations). It chondroitin sulfate proteoglycans were is unusual to associate gap junctions with shown in the RMS pathway (33,57). Since it cell migration, since these require the estab- is possible that the major source of these lishment of complex and intimate adhesive molecules could be the scaffolding glial cells, contacts. Moreover, in the nervous system, tenascin-C and chondroitin sulfate proteo- cell uncoupling, as a rule, is considered to be glycans may somehow prevent migrating a necessary step for initiating migration of cells from straying from the SVZ/RMS path- recent postmitotic neurons (52). However, way (33). However, no obvious defects were pharmacological inhibition of GJIC reduced found in the brains of tenascin-C-deficient migration and proliferation of postnatal SVZ mice (58) albeit effects on SVZ migration cells in vitro (44), suggesting that GJIC is were not specifically addressed. Another pro- positively involved in SVZ/RMS migration. teoglycan, brevican, and a metalloprotein- In the nervous system, the only other ex- ase inhibitor, TIMP-4, are also expressed in ample in which gap junctions were shown to a restricted manner in the postnatal RMS, positively modulate migration is that of neu- suggesting they may also act to guide migra- ral crest cells destined to the heart. For these tion (59). Although proteoglycans and te- sympathetic nerve cells, connexin 43 ge- nascin-C are generally related to inhibitory netic deletion abolished migration (53). Re- effects in process outgrowth, a permissive cently, it has been demonstrated that this role in migration cannot be excluded. How- effect does not require functional coupling, ever, if they do function as inhibitory cues it and may be due to the interaction of connex- is possible that they help elicit chain migra- ins with N-cadherin (54). In most systems tion behavior, since cells would prefer to where gap junctions were shown to be posi- make adhesive contacts essential for migra- tively linked to migration, cells do not mi- tion with other migrating cells rather than grate as individual cells but as cohorts (55), with these substrates in the pathway. as neural crest and RMS cells, suggesting Additional evidence of a role for the that gap junction expression favors adhesion extracellular matrix came after a5 and g1 of these migrating cells. Since GJIC inhibi- were found in the RMS in late em- tion, besides migration, also affects prolif- bryonic and early postnatal stages in rodents eration (44) we postulate that cell coupling (30). These authors also detected several

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subunits in migrating SVZ cells. not being therefore a universal niche for Integrins are an important group of adhesion migration. molecules that bind to the extracellular ma- If the SVZ/RMS cells are under a default trix and have been shown to participate in migratory program, should the SVZ/RMS the migration of progenitors and young neu- function primarily to contain these cells rons (27). In the SVZ/RMS integrin subunits therein? In fact, removing SVZ cells from such as a1, ß1 and ß8 were detected in early their normal sites in vivo and plating them as postnatal ages whereas aV and ß6 subunits explants in vitro does not halt their outward appeared postnatally and persisted to adult- migration (3,26). However, heterotopic trans- hood. Immunoblockade of some of these plantation strategies provide conflicting evi- integrins inhibited the translocation and pro- dence. When injected into the lateral ven- trusion of the leading processes of SVZ cells tricle of the embryonic brain, SVZ cells do (30). Immunoblockade of a6ß1 integrins also not invade the ventricular zone of the cere- disrupts chain migration from EGF expanded bral cortex, but are found in few regions of neurospheres derived from postnatal fore- the brain such as the mesencephalon (25). brain cells (60). On the other hand, young and adult SVZ can invade and disperse in the striatum of the Long and winding road: Instruction adult brain (65). In agreement with a con- or restriction? tainment role for the SVZ/RMS, recent evi- dence indicates that neuroblasts can escape While a complete picture of the mol- the RMS in response to cellular lesions of ecules involved in the RMS flow of cells is neighboring tissue and RMS (66-68). Pres- not available, uncertainty remains as to what ently, we are far from determining the capac- is unique about the SVZ/RMS pathway. ity for autonomous migration of SVZ/RMS Could the plasticity displayed by the SVZ cells. Heterotopic transplantation and post- cells in postnatal life, such as long-range lesion experiments may still prove to be a migration and invasion of differentiated tis- useful strategy to dissect the rich potentiali- sue be conferred to cells transplanted to the ties of these cells for CNS dispersion. SVZ? Or is that capacity exclusive of the SVZ cells? While the SVZ/RMS could sus- Concluding remarks tain migration of some exogenous progeni- tor cell populations (61-63), cells from the The emerging picture is that the appar- embryonic ventricular zone and external ently simple, free migration of these young granular layer failed to migrate when trans- neurons and neuroblasts is the result of the planted into the postnatal SVZ (57,64). In complex interplay of temporally and spa- spite of their normal radial migration it could tially regulated factors, intrinsically coupled be expected that external granular layer and to proliferation, that act upon different as- ventricular zone cells would respond to the pects of the cellular machinery for migra- local cues of the postnatal SVZ/RMS, for, as tion. What gives the olfactory bulb the privi- we have seen above, many factors involved in lege of persistent neuronal addition is still radial migration are also present in RMS mi- unknown. Thus, determining what drives grating cells. Overall, these data suggest that SVZ/RMS migration may not be as impor- SVZ/RMS may provide a permissive/instruc- tant as defining what makes it so spatially tive environment only for responsive cells, restricted.

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