Gliogenic and Neurogenic Progenitorsof the Subventricular Zone: Who AreThey, Where Did They Come From, and

Where Are They Going?CHRISTINE A.G. MARSHALL, SATOSHI O. SUZUKI, AND JAMES E. GOLDMAN*Center for Neurobiology and Behavior, Division of Neuropathology, Department of Pathology,

Columbia University, College of Physicians and Surgeons, New York, New York

KEY WORDS SVZ; astrocyte; oligodendrocyte; glia; forebrain; rostral migratorystream; Zebrin II; Dlx

ABSTRACT The subventricular zone (SVZ) of the perinatal forebrain gives rise toboth neurons and glia. The mechanisms governing the phenotypic specification of pro-genitors within this heterogeneous germinal zone are unclear. However, the character-ization of subpopulations of SVZ cells has given us a better understanding of the basicarchitecture of the SVZ and presents us with the opportunity to ask more detailedquestions regarding phenotype specification and cell fate. Recent work demonstratingthe embryonic origins of SVZ cells is summarized, and a model describing the formationof the perinatal SVZ, noting contributions of cells from pallial as well as subpallialgerminal zones, is presented. We further address differences among classes of SVZ cellsbased on molecular profile, phenotype, and migration behavior and present a modelsummarizing the organization of perinatal SVZ cells along coronal, sagittal, and hori-zontal axes. A detailed description of the SVZ in the adult, outlining classes of cells basedon morphology, molecular profile, and proliferative behavior, was recently reported byDoetsch et al. (Proc Natl Acad Sci USA 93:14895–14900, 1997). Potential relation-ships among cells within the perinatal and adult SVZ will be discussed. GLIA 43:52–61,2003. © 2003 Wiley-Liss, Inc.

INTRODUCTION

Allen (1912) reported the presence of mitotic activitywithin subependymal cells of the postnatal rat forebrainnearly 100 years ago. Later studies of human fetuses(Rydberg, 1932; Kershman, 1938) demonstrated a similarcollection of undifferentiated cycling cells, superficial tothe ependymal layer, lining the lateral ventricles. Opal-ski (1933) and Kershman (1938) suggested that this sub-ependymal layer persists into adulthood as a smallervestigial layer and retains the ability to produce newcells. For this reason, the subependymal layer was con-sidered a potential source of neoplastic cells in maturehumans (Globus and Kuhlenbeck, 1944). Mitotically ac-tive subependymal cells were characterized further inrodents (Bryans, 1959; Smart, 1961; Lewis, 1968b; Alt-man, 1966, 1969; Privat and Leblond, 1972; Sturrock,1985) and primates (Lewis, 1968c).

Microscopic analysis of the subependymal layer re-vealed a division among cells based on morphology(Smart, 1961; Privat and Leblond, 1972). Cells in aborder area, separating the subependymal layer fromthe corpus callosum and caudate, possessed light-stain-ing nuclei, fine processes, and glycogen granules intheir cytoplasms, while many cells within the sub-ependymal layer proper had darker-staining nucleiwith smaller, round cell bodies (Privat and Leblond,

Grant sponsor: National Institutes of Health; Grant number: NS-17125.

*Correspondence to: James E. Goldman, Division of Neuropathology, Depart-ment of Pathology, Columbia University, College of Physicians and Surgeons,P&S 15-420, 630 West 168th Street, New York, NY 10032.E-mail: jeg5@columbia.edu

Received 26 November 2002; Accepted 3 January 2003

DOI 10.1002/glia.10213

GLIA 43:52–61 (2003)

© 2003 Wiley-Liss, Inc.

1972). Darker-nucleated cells typically possessed ahigher labeling index relative to light border cells, asevidenced by the rate of tritiated (3H) thymidine incor-poration (Smart, 1961). The distribution of these celltypes is modulated throughout development, such thatthe neonatal ratio of dark (91%) to light (9%) cellsdecreases as the animal matures. By adulthood, lightnucleated cells comprise roughly 45% of subependymalcells. Interestingly, some cells, which were thought tobe ependymal cells because of their contribution to theventricular wall, have nuclei in a more subependymalposition and contain glycogen granules, a typical fea-ture of astrocytes (Privat, 1972). These cells may, infact, correspond to the type B astrocytic cells currentlythought to possess qualities of neural stem cells(Doetsch et al, 1999).

In an effort to adopt consistent nomenclature amongdevelopmental neurobiologists, the Boulder Committee(1970) used “subventricular zone” (SVZ) to describe thelayer of cells generated superficial to the embryonicventricular zone (VZ) after cortical plate formation.Cells within the SVZ do not undergo interkinetic mi-grations and were thought to be relatively less pluri-potent than neighboring VZ cells (Sidman and Rakic,1973; Takahashi et al., 1995). Perinatally, the SVZcompletely surrounds the lateral ventricles. Further-more, it forms a triangular prominence, bordered bythe subcortical white matter and the developing stria-tum, at the dorsolateral tip of the ventricles. Thisstructure exists at the level of the optic chiasm and canbest be visualized in the coronal plane (Allen, 1912).

The SVZ is highly dynamic in nature. It undergoesan exponential expansion in thickness during the peri-natal period, followed by a marked postnatal reductionin size. Hence, the precise anatomic characterization ofthe SVZ has been elusive. We present a model for theformation of the perinatal SVZ, noting contributions ofcells from pallial as well as subpallial germinal zones.Furthermore, we address differences among classes ofSVZ cells based on phenotype and migration behaviorsand offer a model summarizing the organization ofperinatal SVZ cells along coronal, sagittal, and hori-zontal axes. A detailed model of the adult SVZ, outlin-ing classes of cells based on morphology, molecularprofile, and proliferative behavior, was recently pre-pared by Doetsch et al. (1999). Potential relationshipsamong cells within the perinatal and adult SVZ arediscussed.

ORIGINS OF SVZ CELLS

It has been inferred that SVZ cells are derived fromunderlying VZ cells and migrate directly into the cere-brum (Rakic, 1974, 1988). This holds true for radiallymigrating cells, but many progenitors migrate tangen-tially within the SVZ before emigrating into the over-lying parenchyma (Halliday and Cepko, 1992; Kakitaand Goldman, 1999). Hence, these cells colonize areasof the forebrain far removed from the parent VZ cell.

Increasing evidence of tangential cell migration andmixing of progenitors from germinal zones along thedorsoventral axis raises new questions regarding theembryonic origins of SVZ cells. Studies of tangentialmigration pathways have been reviewed elsewhere(Marin and Rubenstein, 2001; Corbin et al., 2001; Mar-icich et al, 2001) and therefore are not addressed indetail. In summary, cells originating within the ventralbasal ganglia migrate dorsally along tangential routesinto the cerebral cortex and hippocampus from early(embryonic day 11) to late (embryonic day 14–16)stages of embryogenesis (Anderson et al., 2001). Whileearly migrating cells take a lateral route around theSVZ into the intermediate zone of the cortex, late mi-grators follow a medial pathway within the SVZ fromventral to dorsal areas. Hence, cells generated withinthe ganglionic eminences migrate into the dorsolateralSVZ en route to the cortical SVZ and hippocampus.Some of these migrating progenitors express the ven-tral forebrain markers Dlx1/2 (Anderson et al.,1997a,b) and give rise to interneurons, but the fate ofthe entire dorsally migrating population is unknown.As medial tangential migrations from the ganglioniceminences continue into the postnatal period, coincid-ing temporospatially with the expansion of the dorso-lateral SVZ, it is reasonable to believe that progenitorsfrom ventral regions might contribute to this promi-nence.

Recent analyses using molecular markers haveidentified two populations of cells that comprise alarge majority of the perinatal dorsolateral SVZ. Onepopulation is composed of large, polygonal shapedcells situated at the borders of the SVZ that expressZebrin II (aldolase C), a brain-specific isoform offructose 1,6-bisphosphate aldolase. These stationaryZebrin II-expressing border cells possess fine pro-cesses and resemble the light nucleated cells previ-ously described (Smart, 1961; Privat and Leblond,1972). Such cells are morphologically and molecu-larly distinct from a population of smaller, mainlyunipolar, migratory progenitors that reside in thecentral SVZ. For the most part, these unipolar pro-genitors do not express Zebrin II (Staugaitis et al.,2001).

While Zebrin II-expressing cells at the SVZ bordersappear to be derived from the residual VZ, the origin ofthe central migratory population was unclear. It washypothesized that these Zebrin II� cells originate inmore ventral locations and migrate dorsally into theSVZ (Marshall and Goldman, 2002). Many cells withinthe perinatal SVZ then migrate further to give rise toastrocytes and oligodendrocytes throughout the cere-bral cortex, white matter, and striatum (Levison andGoldman, 1993). Glial precursors within the whitematter of the perinatal telencephalon were found to beimmunoreactive for a pan-Dlx antibody, suggestingthat some oligodendrocytes may be derived from Dlx1/2-expressing subpallial cells (He et al., 2001). Hence, aDlx2/tauLacZ knock-in mouse (Corbin et al, 2000) wasused to perform short-term lineage analysis of subpal-

53PROGENITORS OF SUBVENTRICULAR ZONE

lial-derived Dlx2-expressing cells, tracing the fates ofthese cells and their progeny well into postnatal devel-opment (Marshall and Goldman, 2002). Migratory Ze-brin II� cells were identified as the progeny of Dlx2-expressing subpallial cells. Furthermore, Dlx2descendants emigrate postnatally from the SVZ anddevelop into astrocytes and oligodendrocytes withinthe cerebral cortex, white matter, and striatum. Insummary, cells derived from the ganglionic eminencesmigrate dorsally and intermix with Zebrin II-express-ing neuroepithelial cells at the corticostriatal sulcus toform the dorsolateral SVZ. Dlx2 descendants then giverise to glia in the dorsal telencephalon (Fig. 1A).

FORMATION OF THE PERINATAL SVZ

Forebrain expansion during embryogenesis appearsto contribute to the intermixing of these cell popula-tions (Marshall and Goldman, 2002). As the lateral

ganglionic eminence (LGE) enlarges during mid-gesta-tion (E12–14), the pallial VZ folds at an acute angle,forming the corticostriatal sulcus. The sulcus creates awedge-shaped zone of Zebrin II-expressing VZ cells(Fig. 1A, E16). During the subsequent perinatal week,this area undergoes a transformation such that ZebrinII-expressing cells become distributed at the medial,dorsal and lateral periphery of the SVZ, with a largenumber of Zebrin II� cells populating the central re-gion (Staugaitis et al., 2001; Marshall and Goldman,2002). The VZ wedge becomes fenestrated as cells fromsubpallial areas invade it, with the most dorsolateralZebrin II� cells becoming displaced from more medialVZ wedge cells (Fig. 1A, P0). Analyses of the Zebrin IIexpression pattern at each day throughout the perina-tal and early postnatal weeks reveals an accumulationof these migrating cells, progressively displacing theZebrin II� residual neuroepithelium laterally. This em-bryologic displacement should not be confused withmigration. There is no evidence suggesting that thesewedge cells are migratory. Rather, the lateral wedgecells, which form the dorsolateral tip of the SVZ, ap-pear to be relatively stationary.

SPECIFICATION OF SVZ CELLS

How do embryonic origins of SVZ cells influence theirspecification? The SVZ is composed of a heterogeneousmixture of cells from different lineages. Some SVZ cellsbecome specified as astroblasts or oligodendroblasts(Levison and Goldman, 1993; Luskin and McDermott,1994; Parnavelas, 1999). Others remain uncommittedas glioblasts until they migrate into the overlying pa-renchyma, where they diverge into lineages of astro-cytes or oligodendrocytes (Levison et al., 1993; Zerlinand Goldman, submitted). Many SVZ cells appear tocommit to a neuronal lineage and take a rostral migra-tory route toward the olfactory bulb, where they giverise to interneurons (Luskin et al., 1993; Lois and Al-varez-Buylla, 1994). Still, a subset of SVZ cells mayremain multipotent (Fig. 1B). Clonal analyses of pro-genitors isolated from the LGE (He et al., 2001) and thepostnatal dorsolateral SVZ (Levison and Goldman,1997) demonstrate the potential of many of these im-mature cells to give rise to both neurons and glia invitro. Phenotypic specification may occur within theSVZ or even after emigration from the SVZ. In vivo,instructive or permissive factors enable some precursorcells to migrate into the developing cerebrum whileothers remain within the SVZ. The extent to which arelationship exists between migration pathways andfate specification remains unknown.

ORIGINS OF OLIGODENDROCYTES

Recent work has described a ventral origin and spec-ification of telencephalic oligodendrocytes during em-bryonic development (for review, see Woodruff et al.,

Fig. 1. Formation of the perinatal subventricular zone (SVZ). A:E16: Neuroepithelial cells (green) express Zebrin II. A Zebrin II�

wedge of neuroepithelium emerges during corticostriatal sulcus for-mation. This pallial wedge is fenestrated by migratory Dlx2� subpal-lial-derived cells and their progeny; both can be defined by Dlx2/tauLacZ expression (blue). P0: Cells derived from subpallial Dlx2�

cells form the central region of the perinatal SVZ. B: SVZ progenitorsdiverge into separate lineages. The stage at which this lineage ar-borization occurs is unclear.

54 MARSHALL ET AL.

2001). Before birth, progenitors isolated from the ratstriatum have a much greater competence to generateoligodendrocytes in vitro than those harvested fromcerebral cortex. However, progenitors from the postna-tal cerebral cortex have the potential to give rise tosignificant numbers of oligodendrocytes (Birling andPrice, 1998). One popular interpretation of this phe-nomenon is that all oligodendrocyte precursors arespecified by Shh and migrate into the dorsal telenceph-alon during the course of embryogenesis (Woodruff etal., 2001). This interpretation is based on studies inwhich a gradient of DM-20, an alternatively splicedisoform of myelin proteolipid protein, and platelet-de-rived growth factor receptor-� (PDGFR-�) expressionemanates from the anterior entopeduncular area(AEP) and extends into select regions of the telenceph-alon (Pringle and Richardson, 1993; Spassky et al.,1998; Tekki-Kessaris et al., 2001). Further work usingchick/quail and chick/mouse chimeras demonstratesthat many of these early oligodendrocyte precursors,which are specified and differentiate during embryo-genesis, originate within the AEP (Olivier et al., 2001).Moreover, this early population of oligodendrocytes col-onizes the pallidum, striatum, lateral forebrain bundle,and lateral and ventral pallial areas of host telenceph-alon. However, AEP cells do not contribute oligoden-drocytes to dorsal regions of the cerebral cortex.

While this model provides insight into embryonic oli-godendrogenesis, it does not account for those cells spec-ified during the peak of gliogenesis within the first fewpostnatal weeks. Furthermore, it is unclear whether alloligodendrocytes are specified ventrally. Postnatally, pro-genitors emigrate from the SVZ into the striatum andwhite matter as well as the medial, dorsal, and lateralregions of the cerebral cortex, where some develop intooligodendrocytes (Levison and Goldman, 1993; Levison etal., 1993; Luskin and McDermott, 1994). Many of thesecells are not irrevocably committed to an oligodendrocytefate, as SVZ progenitors generate clones containing bothastrocytes and oligodendrocytes in vivo (Levison andGoldman, 1993; Parnavelas, 1999; Zerlin and Goldman,submitted for publication) and mixed neuronal-glialclones in vitro (Levison and Goldman, 1997).

How can one reconcile the ventral specification of oli-godendrocytes with the emergence of both astrocytes andoligodendrocytes from the postnatal SVZ? In one possiblemodel, progenitors originate in the ventral telencephalonand migrate dorsally into the SVZ. Some are specified asoligodendrocyte precursors, while others represent astro-cyte or neuronal precursors, or perhaps remain uncom-mitted. Ventral progenitors, which are competent to formoligodendrocytes but do not yet express common oligoden-drocyte-specific markers, appear to migrate dorsally intothe forming dorsolateral SVZ (Marshall and Goldman,2002). Pringle et al. (1992) observed a lack of PDGFR-�expression by SVZ cells and an upregulation of the recep-tor only by cells that migrated into the surrounding pa-renchyma. Hence, it is possible that cells originating ven-trally become competent to give rise to oligodendrocytesby exposure to extrinsic patterning factors such as Shh

without committing to an oligodendrocyte lineage or nec-essarily expressing early oligodendrocyte markers suchas DM-20 or PDGFR-�. These oligo-competent cells mayremain as multipotent progenitors or glioblasts until theyhave migrated dorsally and taken residence within theSVZ. Alternatively, extrinsic factors within the postnatalSVZ, or even within the white matter or cortex, mightserve to specify oligodendrocytes locally.

ORIGINS OF ASTROCYTES

The perinatal SVZ also generates astrocytes, whichcolonize the cerebral cortex, white matter, and stria-tum (Smart, 1961; Lewis, 1968a; Privat and Leblond,1972; Paterson et al., 1973; Levison and Goldman,1993; Luskin and McDermott, 1994). Zebrin II� pre-cursors that emerge from the central perinatal SVZinitiate Zebrin II expression as they differentiate intoastrocytes but not oligodendrocytes (Staugaitis et al.,2001). Indeed, Zebrin II is specifically expressed byastrocytes in the telencephalon as well as Bergmannglia, Purkinje cells, and astrocytes in the cerebellum ofadult mammals, including humans (Thompson et al.,1982; Kumanishi et al., 1985; Ahn et al., 1994; Waltheret al., 1998). The perinatal SVZ is a secondary source ofastrocytes, temporospatially distinct from the embry-onic ventricular zone (Luskin et al., 1988; Price andThurlow, 1988), which generates astrocytes via a radialglial phenotype (Voigt, 1989). Although astrocytes de-rived from both sources express glial fibrillary acidicprotein (GFAP) and form associations with blood ves-sels and synapses, it is possible that they possess qual-ities making them distinct from one another. The com-parison of diverse classes among Zebrin II-expressingastrocytes may enable us to understand better the rolesastrocytes serve in the normal and pathologic CNS.

MOLECULAR MARKERS DISTINGUISHDIFFERENT POPULATIONS IN THE

PERINATAL SVZ

Within the SVZ, migrating progenitors expressmarkers for undifferentiated neural populations, suchas polysialylated-NCAM (PSA-NCAM), GD3 ganglio-side, and the complex gangliosides recognized by themonoclonal antibody, A2B5 (Levison and Goldman,1997; Ben-Hur et al., 1998; Marshall and Goldman,2002). Neuronal progenitors that give rise to olfactoryinterneurons express neuronal marker such as class III�-tubulin (Menezes and Luskin, 1994) and GABAA re-ceptors (Ma and Barker, 1998; Stewart et al., 2002),even though they are still cycling and migrating in theSVZ and the rostral migratory stream (RMS). Radialglia are positive for astrocytic markers such as vimen-tin, nestin, GLAST, intermediate filament-associatedantigen recognized by RC2 antibody, and brain lipid-binding protein (BLBP) (Misson et al., 1988; Feng etal., 1994; Shibata et al., 1997; Hartfuss et al., 2001;

55PROGENITORS OF SUBVENTRICULAR ZONE

Chanas-Sacre et al., 2000). GFAP is expressed by ra-dial glia in human and primate (Levitt et al., 1981;Choi, 1981), but not in rodent (Pixley and de Vellis,1984) or ferret (Voigt, 1989). Astrocytic and oligoden-drocytic markers, even those considered early markers,i.e. vimentin and GLAST for the former, O4, PDGFR-�and NG2 for the latter, are expressed largely afterprogenitors migrate out of the SVZ into the overlyingwhite matter or the adjacent striatum (Pringle et al.,1992; Zerlin et al., 1995; Staugaitis et al., 2001). Thus,it is difficult to identify and locate progenitors that aredeveloping into either astrocytes or oligodendrocyteuntil they migrate out of the SVZ.

MULTIPLE CELL POPULATIONS IN THEEARLY POSTNATAL SVZ TAKE DISTINCT

MIGRATORY PATHWAYSGlial Progenitors Migrate Primarily Within a

Coronal Plane

Glia, which migrate and differentiate mostly in thepostnatal period, do not colonize the neocortex in awell-organized laminar pattern, like that of neurons.Nevertheless, their migration paths from the SVZ arenot random. When replication-deficient retrovirus ex-pressing a reporter gene was placed in the dorsolateralSVZ at the coronal level crossing the septal nuclei,labeled cells migrate out of the SVZ into the dorsalwhite matter and cortex, the striatum, and, throughthe lateral migratory stream (LMS), into the lateralwhite matter and cortex. Their migration follows thedirection of radial fibers and is primarily confined to acoronal plane, perpendicular to the rostrocaudal axis ofthe SVZ (Fig. 2, P10). All the labeled cells that settledin the cortex, white matter and striatum gave rise toeither astrocytes or oligodendrocytes as determinedmorphologically and immunohistochemically (Levisonand Goldman, 1993; Zerlin et al., 1995; Kakita andGoldman, 1999). Therefore, we infer that this radialmigratory pattern is closely associated with glial fates.However, we cannot completely exclude the possibilitythat late-born neuronal progenitors also take this path-way, but silence the retrovirally transduced reportergene (Pannell and Ellis, 2001; Svoboda et al., 2000). Onoccasion, a very small number of neurons were gener-ated in the neocortex by SVZ cells (Levison and Gold-man, 1993).

Time-lapse video imaging has allowed a direct obser-vation of migrating cells and thus an examination ofthe details and kinetics of glial progenitor migration.Nuclear translocation always occurred in the directionof leading process extension, often leaving a thin trail-ing process behind the cell body. Sometimes movementof process and nuclear translocation were linked, butother times they were independent. Cells moved bidi-rectionally, occasionally migrating back in the direc-tion of the SVZ. A small population turned and mi-grated tangentially in the cortex, parallel to the pialsurface. Migratory velocities were not constant but

were saltatory with periods of inactivity interspersedbetween migratory spurts. The mean velocity wasabout 90 �m/h: therefore, in 3 days after viral infection,we observed a widespread distribution of the labeledcells, with some of them even reaching close to the pia(Kakita and Goldman, 1999).

A GFP-encoding retrovirus was injected at variouscoronal levels of the SVZ to observe the overall migra-tion pattern. Radial migration occurred from all overthe SVZ from the anterior part immediately upstreamof the RMS, referred to as the SVZa (Luskin, 1993), tothe coronal level crossing the dorsal hippocampus.Cells always migrated along the direction of radialfibers, thus primarily confined in a plane around theinjection site (Suzuki and Goldman, in press).

Neuronal Progenitors Migrate Throughout theRostrocaudal Extension of the SVZ

When viewed in sagittal planes, a continuous rostro-caudal stream of labeled cells is observed within theSVZ throughout the rostrocaudal extension of the SVZ,including the RMS (Fig. 2, P10; Suzuki and Goldman,in press). These cells are known to be neuronal progen-itors that give rise to olfactory interneurons (Luskin,1993). Tuj1 immunopositivity was seen all over theSVZ, from the anterior region to the caudal tip at thehippocampal border (our unpublished observations).Time-lapse video imaging showed that these cells mi-grate bidirectionally, parallel to the ventricular sur-face. The occasional cell that strays from the tangentialpath and moves obliquely to encounter the bordersbetween the SVZ and the white matter or the striatum,invariably turns back to stay within the SVZ. Thus, wenever encountered cells migrating rostrocaudally thatthen turned to emigrate radially from the SVZ intoadjacent structures. The migration of this populationappears to be highly restricted within the SVZ untilprogenitors reach the olfactory bulb, where they turndirection and migrate radially into the olfactory cortexto differentiate into interneurons. The finding is con-sistent with the previous observations of an extensivenetwork of pathways for the tangential chain migra-tion of neuronal precursors throughout the lateral wallof the lateral ventricle in the adult mouse brain (Loisand Alvarez-Buylla, 1994; Doetsch and Alvarez-Buylla,1996) (Fig. 2, Adult). Taken all together, we posit thatthe early postnatal SVZ is composed of at least twopopulations, glial and neuronal progenitors, each ofwhich takes a distinct migratory pathway (Fig. 2, P10).

EXTRINSIC FACTORS THAT DETERMINECELL FATES AND MIGRATION BEHAVIOR

What would determine such distinct populations andmigratory behaviors among SVZ cells? Although thereare a growing number of secreted and membrane-bound molecules that play roles in inducing or repress-

56 MARSHALL ET AL.

ing neuronal, astrocytic or oligodendrocytic fates,rather little is know about which of these molecules isexpressed in the SVZ or whether they determine cellfates within the SVZ. Here we discuss some of therelevant factors known to be localized within andaround the SVZ, realizing that a detailed understand-ing of how these molecules are localized and how theyinteract with SVZ progenitors is currently unavailable.

Sonic hedgehog (Shh) and bone morphogenic pro-teins (BMPs), which form opposing gradients of diffus-ible signaling molecules along the dorsoventral axis(Kessaris et al., 2001), respectively promote oligocyto-genesis during embryogenesis at the ventral telenceph-alon in vivo (Tekki-Kessaris et al., 2001) and astrocy-togenesis (Nakashima et al., 2001; Mabie et al., 1997;Mehler et al., 2000). These molecules, in addition to theBMP antagonist, Noggin, are expressed within theSVZ. For example, BMP4 is expressed in SVZ cellsfrom the embryonic period through adulthood, alongwith type I and II BMP receptors, suggestive of anautocrine loop (Gross et al., 1996). In the adult telen-cephalon, BMPs are expressed by SVZ cells, while theantagonist Noggin is expressed by ependymal cells ad-jacent to the SVZ (Lim et al., 2000). Shh has also beenlocalized within the SVZ in the developing brain (Mur-ray et al., 2002).

Notch receptor family proteins have been reportedto promote astrocytogenesis (Tanigaki et al., 2001),while inhibiting oligodendrocytogenesis (Wang et al.,1998) and neurogenesis (Morrison et al., 2000),through binding their ligands Jagged and Delta andactivating signal pathway toward their downstreameffectors, Hes family basic helix-loop-helix genes(Furukawa et al., 2000; Hojo et al., 2000). The role ofNotch in promoting glial fates was reviewed else-where in detail (Gaiano and Fishell, 2002). Expres-sion of Notch1 and its ligands, as well as Hes5, wasshown in the SVZ including the RMS in the develop-ing and the adult brains (Stump et al, 2002). Notchexpression in VZ cells may be important in promot-ing astrocyte development and inhibiting neuronaldevelopment in radial glia (Gaiano et al., 2000).

A number of soluble growth factors have profoundeffects on gliogenesis in vitro and in vivo, the latterdemonstrable in transgenic mouse models. For exam-ple, platelet-derived growth factor (PDGF) is a potentmitogen for oligodendrocyte progenitors (OLPs), andmice overexpressing PDGF demonstrated increasedOLPs and ectopic distribution of mature oligodendro-cytes (Calver et al., 1998). In contrast, mice lackingPDGF-A show a decrease in numbers of PDGFR-��

OLPs in the embryonic period and a dysmyelinationphenotype (tremor) due to a reduction in myelinatingoligodendrocytes after birth (Fruttiger et al., 1999).The sources of PDGF appear to be both neurons andastrocytes (Silberstein et al., 1996), although there iscontroversy about astrocyte expression (Ellison et al.,1996). However, few SVZ cells express PDGFR-� untilthey have migrated out of the SVZ (Pringle et al.,

1992), suggesting that PDGF signaling may not play arole in fate determination within the SVZ itself, butmay be critical in expanding OLP pool size in white andgray matter.

Insulin-like growth factor-1 (IGF-1), which promotesthe survival and differentiation of OLPs, is expressedat the border zone of the early postnatal SVZ (Bartlettet al., 1992), although the specific cellular localizationis not clear. IGF-1-null mice show reduced OPC prolif-eration and development, resulting in decreased myeli-nating oligodendrocytes during early postnatal devel-opment. Mice that overexpress IGF-I in the brainexhibit postnatal brain overgrowth without anatomicabnormality, due to increased neuron and oligodendro-cyte numbers. Whether these phenotypes are due toaltered IGF signaling in SVZ progenitors is unknown,however.

Epidermal growth factor receptor (EGFR) and itsrelated ErbBs are abundantly expressed in the SVZ(Seroogy et al., 1995; Eagleson et al., 1996; Misumi andKawana, 1998; Kornblum et al., 2000). SVZ cells aresensitive to EGF as demonstrated by the dramaticincrease in numbers of SVZ cells produced by injectingEGF into the lateral ventricles (Vaccarino et al., 1999).Thus, the proliferation and possibly the survival of SVZcells is mediated in part by EGF. Basic fibroblastgrowth factor (bFGF), another mitogen for OLPs andfor embryonic neural progenitors, will increase num-bers of cortical glia after intraventricular injections atE20.5 (Vaccarino et al., 1999). Whether and how SVZprogenitors are influenced by bFGF remain unknown.

COMPOSITION OF THE ADULT SVZ ANDNEURAL STEM CELLS

The SVZ continues to produce olfactory interneuronsin adulthood (Altman, 1969; Lois and Alvarez-Buylla,1994). The adult SVZ consists of an extensive networkof pathways for the tangential chain migration of neu-ronal precursors throughout the lateral wall of thelateral ventricle (Lois and Alvarez-Buylla, 1994;Doetsch and Alvarez-Buylla, 1996). This is in line withour observations on the long-distance rostrocaudal mi-gration of neuronal progenitors in the early postnatalSVZ. Doetsch et al. (1997) described the cellular com-position and organization of the SVZ in the adultmouse brain based on electron microscopy. They clas-sified constituent cells into migrating neuroblasts (typeA), astrocytes (type B), cycling precursors (type C),tanycytes (type D), and ependymal cells (type E). Thetype B cells had properties of neural stem cells(Doetsch et al., 1999) that give rise to olfactory inter-neurons in vivo and multipotent neurospheres in vitro.

Johansson et al. (1999) provided evidence that ependy-mal cells give rise to olfactory interneurons and spinalastrocytes. Because some reports appear to rule out thepossibility that ependymal cells are stem cells (Chiasson

57PROGENITORS OF SUBVENTRICULAR ZONE

et al., 1999; Laywell et al., 2000; Capela and Temple,2002), and another study suggested both astrocytes andependymal cells could serve as stem cells (Rietze et al.,2001), the subject remains controversial.

Adult SVZ cells also give rise to glia in vitro (Lois andAlvarez-Buylla, 1994; Doetsch et al., 1999). Migrationof glial progenitors from the SVZ to the neocortexceases by P14 (Levison and Goldman, 1993). Whilegliogenesis in the adult white matter and cortex hasbeen demonstrated both in vivo and in vitro (Gensertand Goldman, 1996); Levison and Goldman, 1997;Gensert and Goldman, 2001), it is unclear whetheradult SVZ cells give rise to glia in vivo.

REGIONALIZATION WITHIN THE SVZ

Why might the SVZ cease to produce glial cells dur-ing adulthood? BMPs, as well as their cognate recep-tors, are expressed within the perinatal SVZ and aresufficient to specify perinatal SVZ cells to become as-trocytes at the expense of neurons and oligodendro-cytes (Gross et al., 1996). Starting around P7 in themouse, the neuroepithelium matures into ciliatedependymal cells and subventricular astrocytes (Bruni,1998; C. Marshall, unpublished observations). Ependy-mal cells secrete the bone morphogenetic protein(BMP) antagonist Noggin, which inhibits the gliogenic

Fig. 2. Migration of subventricular zone (SVZ) cells in the neonataland adult brain. P10: Astrocytic and oligodendrocytic progenitors, atleast partly derived from Dlx� cells, do not actively migrate rostro-caudally within the SVZ. They start emigration (green lines, shownfor just one coronal plane) from the SVZ (yellow zones) toward thewhite matter, cortex and the striatum utilizing local radial glial fibersas migratory scaffolds. Neuronal progenitors, which are polysialy-lated-NCAM (PSA-NCAM)�/Tuj1� (blue line), migrate rostrallywithin the SVZ all over the wall of the lateral ventricle toward theolfactory bulb to give rise to periglomerular and granular interneu-

rons. They remain within the SVZ until they reach the olfactory bulb,where they turn and migrate radially into the olfactory cortex. Bothglial and neuronal progenitors may migrate bidirectionally until theysettle in their final destination. Adult: The genesis of neuroblasts andtheir migration toward the olfactory bulb continues throughout life. Inadulthood, the route of neuronal migration appears as an anastomos-ing migratory network (blue lines) within the SVZ all over the lateralwall of the lateral ventricle, ensheathed by astrocytes derived fromZebrin II� neuroepithelial cells.

Fig. 3. Regionalization of the subventricular zone (SVZ). The SVZcan be delineated into two subpopulations of cells based on the ex-pression of Zebrin II (green) or the Dlx2/tauLacZ reporter (blue).Zebrin II� residual VZ cells form the outer borders of the SVZ. Cellssharing a Dlx2-expressing subpallial origin, as defined by Dlx2/tauL-acZ (�gal) expression, populate the central SVZ. These cells give riseto interneurons in the olfactory bulb from the perinatal periodthroughout adulthood. SVZ progenitors also generate astrocytes and

oligodendrocytes, which colonize the striatum, white matter, and ce-rebral cortex during the peak of gliogenesis (first several postnatalweeks). Noggin (yellow shading) expression by ependymal cells (pink)creates a neurogenic niche along the walls of the lateral ventricles.The postnatal dorsolateral SVZ contains neurogenic and gliogenicniches, while the adult SVZ appears to be entirely neurogenic undernormal conditions.

58 MARSHALL ET AL.

activity of BMPs and creates a neurogenic niche withinthe SVZ along the walls of the lateral ventricles (Lim etal., 2000). As there are fewer mature ependymal cellspresent during the peak of gliogenesis (P10) than dur-ing adulthood, it is reasonable to suggest that lessNoggin is present within the perinatal SVZ than in theadult (Fig. 3). Furthermore, because the perinatal SVZis much larger in area than the adult SVZ, Nogginexpression influences a smaller proportion of SVZ cells,allowing more to respond to BMPs and adopt glialphenotypes. Interestingly, expression of BMP-4, whichis strongly inhibited by Noggin, is upregulated perina-tally within the SVZ and maintained throughout post-natal development into adulthood (Gross et al., 1996),where it is expressed primarily by SVZ astroctyes (Limet al., 2000). The adult SVZ is a vestigial structure dueto the limited requirement for newly generated cells inthe mature brain (Opalski, 1933; Kershman, 1938),hence the mature ependyma produces enough Nogginto diffuse throughout the entire SVZ (Lim et al., 2000),creating a primarily neurogenic germinal zone undernormal conditions.

Such a model is supported by the migration patternsof SVZ cells discussed earlier as well as by molecularexpression patterns of SVZ cells. Glial-specific molecu-lar markers such as Olig-2, vimentin, PDGFR-� andNG2 are expressed by cells residing within the lateralregions of the perinatal SVZ (as well as by cells thathave begun to migrate from the SVZ) but not by cellsnear the developing ependymal lining (C. Marshall,unpublished observations). A halo of Olig-2 expressionappears at the dorsal and lateral borders of the SVZperinatally. This expression expands dorsally into thewhite matter and all layers of the cerebral cortex andlaterally into the striatum throughout the first severalpostnatal weeks. Interestingly, both astrocytes as wellas oligodendrocytes express Olig-2 in the white matter,cortex, and striatum; however, the central SVZ andRMS are relatively devoid of Olig-2 expression (C. Mar-shall, unpublished observations). This recent data,taken together with other work described above, sug-gests that a glial compartment may exist within thedorsolateral limits of the perinatal SVZ. Recent studiesof transcription factors that regulate the specificationof neural progenitors (for review, see Morrison, 2001;Bertrand et al., 2002) promise to deepen our under-standing of the complex cell architecture within theSVZ. By identifying the genetic pathways that specifySVZ cells, we will be able to examine further the rela-tionship between phenotype and migratory behavior.

ACKNOWLEDGMENTS

The authors thank Gord Fishell and Josh Corbin forthe generous gift of Dlx2/tauLacZ mutant tissue, JohnRubenstein and Stewart Anderson for the Dlx2 anti-body, Carol Mason for graciously sharing imagingequipment, and Akiyoshi Kakita for help with time-lapse video microscopy. This work was supported by

National Institutes of Health grant NS-17125 (toJ.E.G.).

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