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Mechanism of migration of olfactory bulb interneurons
seminars in
CELL & DEVELOPMENTAL BIOLOGY, Vol 8, 1997: pp 207–213
Mechanism of migration of olfactory bulb interneurons Arturo Alvarez-Buylla
these olfactory interneuron precursors utilize a specialized form of neuronal migration that is unlike radial glial- or axonal- guided migration.5 Here I briefly review how the olfactory bulb is formed and the evidence indicating that olfactory bulb interneurons utilize a specialized form of neuronal migration to reach their target.
Neuroblasts in the subventricular zone of the walls of the lateral ventricle in the brain of young and adult rodents migrate into the olfactory bulb where they differentiate into local interneurons. These cells move closely associated with each other, forming chains without radial glial or axonal guidance. The migrating neuroblasts express PSA-NCAM on their surface and PSA residues are crucial for cell–cell interaction during chain migration. This migration occurs throughout the lateral wall of the lateral ventricle, where the precursors form an extensive network of chains. Cells remain organized as chains until they reach the olfactory bulb, where they disperse organized as chains until they reach the olfactory bulb, where they disperse radially as individual cells. Chain migration defines a novel form of neuronal precursor translocation which is based on homotypic interactions between cells.
Histogenesis of the olfactory bulb The olfactory bulb forms at the rostral end of the forebrain. In the rat a small protrusion in the anterior telencephalic vesicle corresponding to the emerging olfactory bulb forms around embryonic day 12 (E12).6 During these early stages, axons from olfactory receptor neurons reach into the anterior telencephalon, and their arrival correlates with a change of the mitotic rate of the neuroepithelium resulting in the initial bulging of the olfactory bulb.7 Subsequently, the bulb ventricular zone (VZ) enlarges and is thought to produce waves of neurogenesis resulting in the initial set of olfactory bulb neurons. These processes occur rapidly between E13 and P1 in the rat.6,8 The olfactory bulb output neurons (projection neurons) are produced first: mitral cells are born between E11 and E13 and tufted cells are formed between E13 and E18. The mitral cell layer first appears at around E15 and this is the first indication of the laminar structure of the olfactory bulb. By E18, glomerular and external plexiform layers have formed and the first glomeruli appear. In many rodents the olfactory bulb ventricle collapses soon after birth and the VZ disappears. In addition to the projection neurons, the olfactory bulb has a tremendous number of interneurons. Olfactory bulb interneurons are found predominantly in the granular layer, but many are also localized around glomeruli and in the mitral cell layer. [3H]-thymidine experiments indicate that interneurons begin to be born around E15. The first evidence of differentiated interneurons occurs in the granular layer around E18.8 However, unlike the projection neurons of the olfactory bulb, interneurons continue to be produced postnatally and into adult life.8-12 At
Key words: granular neuron / NCAM / neurogenesis / neuronal migration / olfaction ©1997 Academic Press Ltd
THE OLFACTORY BULB is the first relay for olfactory information within the CNS. This brain region contains a very large population of small interneurons, called granule neurons. These cells regulate the activity of mitral and tufted cells and play a key role in olfactory learning (see ref 1 for review). Granule neurons are of particular interest because they are continually produced postnatally. Adult neurogenesis may be related to neural plasticity2 and suggest new strategies for brain repair. In addition, the production of neurons in the juvenile and adult brain raises questions about the mechanism of neuronal birth, migration and differentiation. Olfactory bulb interneurons arise from a pool of proliferating cells outside of the olfactory bulb in the subventricular zone (SVZ) of the walls of the lateral ventricles. Cells from this proliferative pool migrate tangentially for a long distance to reach the olfactory bulb.3,4 Several recent lines of evidence indicate that From The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA ©1997 Academic Press Ltd 1084-9521/97/020207 + 07 $25.00/0/sr960134
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A. Alvarez-Buylla (Figure 1). These labeling studies indicate that the vast majority of migrating cells form olfactory granular neurons, while a smaller proportion generate periglomerular cells. SVZ cells continue to proliferate postnatally not only in the anterior forebrain but also throughout the lateral wall of the lateral ventricles.15 Retroviral labeling studies in neonatal rats3 suggest that only cells in the anterior SVZ migrate to the olfactory bulb, whereas SVZ cells that proliferate in the posterior lateral ventricle generate glial cells. However, in-vitro studies indicate that SVZ cells in the posterior lateral ventricle of the adult rat can generate neurons.19 Recent work shows that in the SVZ of the lateral wall of the lateral ventricle of adult mice there is an extensive network of tangentially migrating neuronal precursors29 (Figure 1). Most of these precursors form chains (below and Figure 2) that orient along the longitudinal axis of the lateral ventricle and many of these chains join the RMS. Moreover, DiI labeling of the caudal SVZ and transplantation experiments in the caudal SVZ indicate that cells originating in intermediate and posterior regions of the lateral wall of the lateral ventricle also migrate to the olfactory bulb and differentiate into neurons. Precursors for olfactory bulb interneurons, therefore, are found throughout the SVZ. It is remarkable that such an extensive area of SVZ covering most of the lateral wall
birth, all the olfactory bulb layers are formed, but the bulb continues to grow postnatally, due largely to an increase in the numbers of granular neurons.10,13 Mitral and tufted cells are thought to be born in the VZ of the embryonic olfactory bulb.6 In contrast, interneurons of the olfactory bulb (granular and periglomerular neurons) originate from a proliferative layer outside the bulb.
Migration of cells from the subventricular zone (SVZ) of the lateral ventricle into the olfactory bulb The SVZ is a layer of proliferating cells that forms adjacent to the ventricular zone during embryonic development, and is classically considered the site of birth of many of the neuroglia in the brain.14 Unlike germinal cells in the ventricular zone that are radially organized,14 SVZ cells have no apparent organization.15 Cell division stops in the VZ sometime around birth, but proliferation persists in the SVZ of the lateral ventricles into adult life.15-18 In-vitro studies have demonstrated that proliferating SVZ cells isolated from adults can differentiate into neurons.18,19 The fate of proliferating SVZ cells in vivo, however, has been controversial. Early work inferred, using systemic injections of [3H]-thymidine,9,20 that one important target of postnatally generated SVZ cells was the olfactory bulb,9 but it was also suggested that SVZ cells migrated into neocortex and striatum where they generated neurons. Systemic administration of [3H]-thymidine alone, however, do not allow the precise localization of the site of origin or the fate of migrating young neurons. Other work has suggested that postnatally proliferating SVZ cells give rise to glial cells,21-28 or that SVZ cells die soon after mitosis.15,17 Recent studies that trace the migration of a restricted cohort of SVZ cells in neonatal3 and adult4 rodent brain have demonstrated that SVZ cells migrate to the olfactory bulb where they differentiate into neurons. Localized injections of [3H]-thymidine,4 dyes,4 retroviruses3 or transplantation of small fragments of genetically labeled SVZ cells into the anterior SVZ4 results in labeled neurons in the olfactory bulb, but not in other brain regions. This is consistent with the observation that migration occurs along a restricted pathway called the rostral migratory stream (RMS)9 that extends along the dorsal and rostral edge of the anterior horn of the lateral ventricle, which then curves ventrally and then rostrally to invade the core of the olfactory bulb
Figure 1. Schematic sagittal view of the adult mouse brain showing the exposed lateral wall of the lateral ventricle (shaded area) and migratory pathways of neuronal precursors destined to the olfactory bulb. The SVZ of the lateral wall of the lateral ventricle is organized as a network of chains (Fig. 2A)28 (lines on shaded area) many of which join the rostral migratory stream (RMS). Cells in the RMS migrate rostrally into the core of the olfactory bulb from where they disperse radially (thin arrows) and differentiate into granular and periglomerular neurons.2,3 M, foramen of Monro; NC, neocortex; CB, cerebellum; cc, corpus callosum; OB, olfactory bulb.
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Chain migration of olfactory bulb interneurons that this molecule is highly enriched in the RMS,30,36,38 where it is present on the surface of the migrating cells. Close examination of the staining pattern reveals that migrating cells positive for PSANCAM are organized as long cords of cells (Figure 2), or chains.30 Knockout mice in which the PSA-NCAM (180 Kb exon) is deleted,39 or mice in which the entire NCAM gene has been rendered inactive,40 have a major defect in the tangential migration of neuronal precursors to the olfactory bulb. Interestingly, these mice show very minor defects in overall histogenesis of the brain, however, the olfactory bulbs are drastically reduced in size and SVZ cells accumulate close to the anterior lateral ventricle. Closer analysis of NCAMmutant mice indicates that there is a drastic reduction in the forward migration of olfactory bulb precursors from the SVZ.41 Transplantation experiments suggest that the defect in the migration of olfactory bulb precursors in the NCAM-mutant mice is not cell autonomous.42 Mutant cells grafted to the SVZ of wild-type mice are able to migrate to the olfactory bulb. Therefore, the grafted cells attach to host cells that express PSA-NCAM normally on their surface and are carried along into the olfactory bulb. Alternatively, the expression of this surface molecule on
of the lateral ventricle serves as a germinal layer for olfactory bulb interneurons. It is likely that a similar network of tangential pathways exists throughout the SVZ of neonatal animals and that similar tangential SVZ pathways exist in the embryo. In adult mice, neuronal precursors may migrate as much as 8 mm before reaching their target. The number of cells migrating at any one time has not been determined, but judging from the size of the RMS in the neonatal brain, a massive number of cells migrate along this pathway. Even in the adult, many cells continue to traverse the RMS; at least 10,000 and 20,000 cells enter the RMS every few hours.4 Precursors in the RMS migrate at an average rate of 20–30 µm/h4 which is four to five times faster than radially migrating cells in the cortex.14 Another interesting feature of the migrating neuronal precursors is that they continue to divide during migration30,31 even after they begin expressing neuronal markers.32 This is unlike all other young neurons described in the mammalian CNS.
Mechanism of neuronal migration in the SVZ and RMS Migrating cells in the RMS have an elongated morphology33 with a long leading process. This leading process ends in a growth cone similar to those found at the tip of growing axons. In some cells, a short stubby trailing process is also observed. The majority of the growth cone-containing leading processes in the RMS are oriented in the direction of migration, suggesting that this structure plays an important role for neuronal translocation. Cell adhesion molecules have been suggested to mediate cell–cell interaction during neuronal migration.34 Important clues about the mechanism of migration of olfactory bulb precursors come from studies of the polysialylated neural cell adhesion molecule, PSA-NCAM. PSA-NCAM has multiple homopolymers of alpha-2-8 linked sialic acid (PSA) that make up as much as 30% of the weight of the molecule. This heavy glycosylation is thought to reduce cell adhesion,35 perhaps facilitating cell movements during histogenesis and morphogenesis. Consistent with this view, PSA-NCAM, also known as embryonic NCAM, is highly expressed during embryonic development. However, PSA-NCAM is also expressed in the juvenile and adult brain at sites thought to undergo plastic changes.36,37 Staining with antibodies that recognize PSA-NCAM demonstrate
Figure 2. Chains of migrating neuronal precursors destined for the olfactory bulb reveal a novel form of neuronal migration. (A) Migrating young neurons are organized as chains as revealed by PSA-NCAM immunostaining. This micrograph shows part of the extensive network of chains present in the lateral wall of the lateral ventricle in adult mice.28 (B) Schematic representation of a chain of migrating neuroblasts. During chain migration, neuroblasts (in gray) migrate closely associated to each other without radial glia or axonal guides. These chains of migrating cells are ensheathed by the cell bodies and processes of glial cells (in black) that form a tube-like structure.
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A. Alvarez-Buylla Chain migration represents a novel form of neuronal movement in which no radial glia or axonal processes are used. Instead, cells migrate associated with each other. When cells from the developing cerebral cortex44 or cerebellum,45 which normally migrate along radial glial processes, are grafted into the anterior SVZ, they do not migrate into the RMS. Instead, these cells differentiate close to their site of implantation. This result strengthens the notion that chain migration is a specialized form of neuronal translocation used by specific cell types. It also suggests that the cell surface signals used for radial migration differ from those used for chain migration. The majority of neuronal precursors in the RMS are oriented toward the olfactory bulb, suggesting that directional clues exist along this pathway. The orientation of cells may be due to an endogenous polarization of the migrating cells within the RMS or may be induced by chemoattractive or chemorepulsive gradients. One possibility is that the olfactory bulb secretes an attractant molecule responsible for the directional migration of its precursors. However, this does not appear to be the case; SVZ cells do not orient toward a piece of olfactory bulb in culture,46 and in vivo, olfactory bulb removal does not prevent the forward migration of neuronal precursors (Kirschenbaum and Alvarez-Buylla, unpublished observation). Interestingly, there is recent evidence for a chemorepulsive activity in the caudal septum.46 SVZ explants placed in a collagen gel a short distance from an explant isolated from the caudal septum, show asymmetrical migration, with the majority of the cells migrating from the side of the explant furthest from the septum. A similar chemorepulsive activity on SVZ is demonstrated in the embryonic floor plate of the spinal cord.46 The identity of the repellent substance and a role for a chemorepulsive substances in vivo remains to be demonstrated. It is noteworthy that in the adult brain the majority of precursors come from the wall of the ventricle opposite to the side where the septum is found.29 The function of the glial trabecula surrounding chains of migrating cells in the RMS of adult mice remains unknown. These glial cells could impose a mechanical barrier to prevent migration outside of the RMS. In addition, RMS glia may isolate migrating cells from substances in the surrounding brain parenchyma or could themselves provide factors important for the survival, differentiation or directional movement of the migrating neuroblasts.
cells in the migratory environment may be sufficient to allow movement of the mutant cells. Conversely, transplants of wild-type cells into mutant animals result in absence of migration, highlighting the importance of cell–cell interaction and environment in the migration of these neuronal precursors. It has been shown that enzymatic removal of PSA from NCAM by endosialidase injections into the neonatal anterior forebrain phenocopy the observed migratory defect observed in the NCAM-mutant mice.41 Together, these experiments highlight the importance of the PSA residues for the tangential migration of the olfactory bulb interneuron precursors. Results from the NCAM-mutant mice and the organization of neural precursors as chains, suggest that cell–cell interaction plays an important role in their migration. Chains may correspond to arrays of neuronal precursors following one or multiple guiding processes (e.g. from radial glia or axons that extend along the RMS). However, immunocytochemical and dye labeling experiments have failed to show axonal or radial glial processes in the RMS. Instead the RMS of adult mice is composed of two types of cells:43 type A cells correspond to the migrating neuroblasts, and type B cells that based upon their ultrastructure and high content of glial fibrillary acidic protein (GFAP), are astrocytes. Serial sectioning of the RMS in sagittal and frontal planes and reconstruction of the images reveal an interesting topographical arrangement of type A and B cells (Figure 2C). Chains are formed by the cell bodies and processes of type A cells only. None of the processes of type B cells, or for that matter any other cell type with the exceptions of type A cells, are found inside the chains. Type B cells are more dispersed, but are clearly confined to the RMS. They have multiple branching processes loosely oriented in the direction of migration. The processes of these astrocytes form a tubular trabecula that ensheaths the chains of migrating cells. Therefore, during chain migration, young neurons seem to move closely associated to each other through a ‘tunnel’ formed by the processes of glial cells. Migrating cells establish very close contacts, including small specialized junctions, amongst themselves, but not with the surrounding glia, suggesting that homophilic interaction between migrating cells are critical for this migration. Consistent with this interpretation, small explants of neonatal SVZ grown in culture give rise to chain-like structures.42 Cells in the in-vitro chains migrate away from the explant presumably by association with each other. 210
Chain migration of olfactory bulb interneurons
Perspective
moving tightly apposed to each other forming chains through the juvenile and adult brain. Chain migration, however, is only part of the story behind olfactory bulb interneuron’s continual addition and replacement. Many questions still remain, such as, how is such a long migration established and maintained; why is interneuron replacement in the juvenile and adult brain olfactory bulb necessary; and what is the nature and location of the stem cell population that supports the continual production of interneurons in the adult brain. This and other questions address basic principles of neuronal formation and are likely to reveal novel mechanisms for brain plasticity and brain repair.
Chain migration is a mechanism of movement of neuronal precursors based upon homotypic interactions that require no axonal or radial glia tracks. This form of migration is used in the postnatal brain by cells moving in the tangential plane. Tangential neuronal migration has also been demonstrated in the embryo,47-51 but the corresponding mechanism of cell movement is not known. Chain migration may be used by neural precursors in the developing brain and could explain certain forms of tangential dispersal. In order to determine how widespread chain migration is in the embryonic and adult brain, markers that are specifically related to chain migration need to be identified. In addition to PSA-NCAM, studies have shown that the RMS is rich in other molecules, including extracellular matrix components and glycoproteins such as tenascin, chodriotin sulfate, CD24 and 9-O-acetylated gangliosides.52-54 However, no marker exclusive to chain migration is currently available. The challenge ahead is to determine the nature of the homophilic interactions between migrating young neurons and the precise role of PSA-NCAM during chain migration. In addition to the identification of molecules related to chain migration, techniques to genetically manipulate the neuronal precursors in the SVZ are required. Recent evidence suggests that adenovirus may provide an efficient means of introducing genes into cells in the SVZ.55 This will allow direct testing of the role of different genes in the migration and differentiation of these cells. In addition to a molecular approach and in order to determine how cells actually move during chain migration, new in-vitro and in-vivo techniques are needed to visualize the behavior of neuroblasts in chains. The SVZ and the migratory pathway to the olfactory bulb in the juvenile and adult brain offer a unique system with which to study neuronal migration. Unlike the embryonic brain, the postnatal CNS is more accessible for experimental manipulation; cell migration is not distorted by major morphogenetic displacements, and neuronal production occurs over a long period of time. These properties make the SVZ and the pathway to the olfactory bulb very attractive systems with which to study the mechanism of neuronal movement and guidance, as well as the mechanism of neuronal differentiation. Studies on the origins of olfactory bulb interneurons thus reveal a remarkable traffic of cells,
Acknowledgement I am grateful to Joanne Conover and Daniel Lim for their suggestions on the manuscript. Work was supported by grant NS32116 from the NICHD of the NIH.
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CELL & DEVELOPMENTAL BIOLOGY, Vol 8, 1997: pp 207–213
Mechanism of migration of olfactory bulb interneurons Arturo Alvarez-Buylla
these olfactory interneuron precursors utilize a specialized form of neuronal migration that is unlike radial glial- or axonal- guided migration.5 Here I briefly review how the olfactory bulb is formed and the evidence indicating that olfactory bulb interneurons utilize a specialized form of neuronal migration to reach their target.
Neuroblasts in the subventricular zone of the walls of the lateral ventricle in the brain of young and adult rodents migrate into the olfactory bulb where they differentiate into local interneurons. These cells move closely associated with each other, forming chains without radial glial or axonal guidance. The migrating neuroblasts express PSA-NCAM on their surface and PSA residues are crucial for cell–cell interaction during chain migration. This migration occurs throughout the lateral wall of the lateral ventricle, where the precursors form an extensive network of chains. Cells remain organized as chains until they reach the olfactory bulb, where they disperse organized as chains until they reach the olfactory bulb, where they disperse radially as individual cells. Chain migration defines a novel form of neuronal precursor translocation which is based on homotypic interactions between cells.
Histogenesis of the olfactory bulb The olfactory bulb forms at the rostral end of the forebrain. In the rat a small protrusion in the anterior telencephalic vesicle corresponding to the emerging olfactory bulb forms around embryonic day 12 (E12).6 During these early stages, axons from olfactory receptor neurons reach into the anterior telencephalon, and their arrival correlates with a change of the mitotic rate of the neuroepithelium resulting in the initial bulging of the olfactory bulb.7 Subsequently, the bulb ventricular zone (VZ) enlarges and is thought to produce waves of neurogenesis resulting in the initial set of olfactory bulb neurons. These processes occur rapidly between E13 and P1 in the rat.6,8 The olfactory bulb output neurons (projection neurons) are produced first: mitral cells are born between E11 and E13 and tufted cells are formed between E13 and E18. The mitral cell layer first appears at around E15 and this is the first indication of the laminar structure of the olfactory bulb. By E18, glomerular and external plexiform layers have formed and the first glomeruli appear. In many rodents the olfactory bulb ventricle collapses soon after birth and the VZ disappears. In addition to the projection neurons, the olfactory bulb has a tremendous number of interneurons. Olfactory bulb interneurons are found predominantly in the granular layer, but many are also localized around glomeruli and in the mitral cell layer. [3H]-thymidine experiments indicate that interneurons begin to be born around E15. The first evidence of differentiated interneurons occurs in the granular layer around E18.8 However, unlike the projection neurons of the olfactory bulb, interneurons continue to be produced postnatally and into adult life.8-12 At
Key words: granular neuron / NCAM / neurogenesis / neuronal migration / olfaction ©1997 Academic Press Ltd
THE OLFACTORY BULB is the first relay for olfactory information within the CNS. This brain region contains a very large population of small interneurons, called granule neurons. These cells regulate the activity of mitral and tufted cells and play a key role in olfactory learning (see ref 1 for review). Granule neurons are of particular interest because they are continually produced postnatally. Adult neurogenesis may be related to neural plasticity2 and suggest new strategies for brain repair. In addition, the production of neurons in the juvenile and adult brain raises questions about the mechanism of neuronal birth, migration and differentiation. Olfactory bulb interneurons arise from a pool of proliferating cells outside of the olfactory bulb in the subventricular zone (SVZ) of the walls of the lateral ventricles. Cells from this proliferative pool migrate tangentially for a long distance to reach the olfactory bulb.3,4 Several recent lines of evidence indicate that From The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA ©1997 Academic Press Ltd 1084-9521/97/020207 + 07 $25.00/0/sr960134
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A. Alvarez-Buylla (Figure 1). These labeling studies indicate that the vast majority of migrating cells form olfactory granular neurons, while a smaller proportion generate periglomerular cells. SVZ cells continue to proliferate postnatally not only in the anterior forebrain but also throughout the lateral wall of the lateral ventricles.15 Retroviral labeling studies in neonatal rats3 suggest that only cells in the anterior SVZ migrate to the olfactory bulb, whereas SVZ cells that proliferate in the posterior lateral ventricle generate glial cells. However, in-vitro studies indicate that SVZ cells in the posterior lateral ventricle of the adult rat can generate neurons.19 Recent work shows that in the SVZ of the lateral wall of the lateral ventricle of adult mice there is an extensive network of tangentially migrating neuronal precursors29 (Figure 1). Most of these precursors form chains (below and Figure 2) that orient along the longitudinal axis of the lateral ventricle and many of these chains join the RMS. Moreover, DiI labeling of the caudal SVZ and transplantation experiments in the caudal SVZ indicate that cells originating in intermediate and posterior regions of the lateral wall of the lateral ventricle also migrate to the olfactory bulb and differentiate into neurons. Precursors for olfactory bulb interneurons, therefore, are found throughout the SVZ. It is remarkable that such an extensive area of SVZ covering most of the lateral wall
birth, all the olfactory bulb layers are formed, but the bulb continues to grow postnatally, due largely to an increase in the numbers of granular neurons.10,13 Mitral and tufted cells are thought to be born in the VZ of the embryonic olfactory bulb.6 In contrast, interneurons of the olfactory bulb (granular and periglomerular neurons) originate from a proliferative layer outside the bulb.
Migration of cells from the subventricular zone (SVZ) of the lateral ventricle into the olfactory bulb The SVZ is a layer of proliferating cells that forms adjacent to the ventricular zone during embryonic development, and is classically considered the site of birth of many of the neuroglia in the brain.14 Unlike germinal cells in the ventricular zone that are radially organized,14 SVZ cells have no apparent organization.15 Cell division stops in the VZ sometime around birth, but proliferation persists in the SVZ of the lateral ventricles into adult life.15-18 In-vitro studies have demonstrated that proliferating SVZ cells isolated from adults can differentiate into neurons.18,19 The fate of proliferating SVZ cells in vivo, however, has been controversial. Early work inferred, using systemic injections of [3H]-thymidine,9,20 that one important target of postnatally generated SVZ cells was the olfactory bulb,9 but it was also suggested that SVZ cells migrated into neocortex and striatum where they generated neurons. Systemic administration of [3H]-thymidine alone, however, do not allow the precise localization of the site of origin or the fate of migrating young neurons. Other work has suggested that postnatally proliferating SVZ cells give rise to glial cells,21-28 or that SVZ cells die soon after mitosis.15,17 Recent studies that trace the migration of a restricted cohort of SVZ cells in neonatal3 and adult4 rodent brain have demonstrated that SVZ cells migrate to the olfactory bulb where they differentiate into neurons. Localized injections of [3H]-thymidine,4 dyes,4 retroviruses3 or transplantation of small fragments of genetically labeled SVZ cells into the anterior SVZ4 results in labeled neurons in the olfactory bulb, but not in other brain regions. This is consistent with the observation that migration occurs along a restricted pathway called the rostral migratory stream (RMS)9 that extends along the dorsal and rostral edge of the anterior horn of the lateral ventricle, which then curves ventrally and then rostrally to invade the core of the olfactory bulb
Figure 1. Schematic sagittal view of the adult mouse brain showing the exposed lateral wall of the lateral ventricle (shaded area) and migratory pathways of neuronal precursors destined to the olfactory bulb. The SVZ of the lateral wall of the lateral ventricle is organized as a network of chains (Fig. 2A)28 (lines on shaded area) many of which join the rostral migratory stream (RMS). Cells in the RMS migrate rostrally into the core of the olfactory bulb from where they disperse radially (thin arrows) and differentiate into granular and periglomerular neurons.2,3 M, foramen of Monro; NC, neocortex; CB, cerebellum; cc, corpus callosum; OB, olfactory bulb.
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Chain migration of olfactory bulb interneurons that this molecule is highly enriched in the RMS,30,36,38 where it is present on the surface of the migrating cells. Close examination of the staining pattern reveals that migrating cells positive for PSANCAM are organized as long cords of cells (Figure 2), or chains.30 Knockout mice in which the PSA-NCAM (180 Kb exon) is deleted,39 or mice in which the entire NCAM gene has been rendered inactive,40 have a major defect in the tangential migration of neuronal precursors to the olfactory bulb. Interestingly, these mice show very minor defects in overall histogenesis of the brain, however, the olfactory bulbs are drastically reduced in size and SVZ cells accumulate close to the anterior lateral ventricle. Closer analysis of NCAMmutant mice indicates that there is a drastic reduction in the forward migration of olfactory bulb precursors from the SVZ.41 Transplantation experiments suggest that the defect in the migration of olfactory bulb precursors in the NCAM-mutant mice is not cell autonomous.42 Mutant cells grafted to the SVZ of wild-type mice are able to migrate to the olfactory bulb. Therefore, the grafted cells attach to host cells that express PSA-NCAM normally on their surface and are carried along into the olfactory bulb. Alternatively, the expression of this surface molecule on
of the lateral ventricle serves as a germinal layer for olfactory bulb interneurons. It is likely that a similar network of tangential pathways exists throughout the SVZ of neonatal animals and that similar tangential SVZ pathways exist in the embryo. In adult mice, neuronal precursors may migrate as much as 8 mm before reaching their target. The number of cells migrating at any one time has not been determined, but judging from the size of the RMS in the neonatal brain, a massive number of cells migrate along this pathway. Even in the adult, many cells continue to traverse the RMS; at least 10,000 and 20,000 cells enter the RMS every few hours.4 Precursors in the RMS migrate at an average rate of 20–30 µm/h4 which is four to five times faster than radially migrating cells in the cortex.14 Another interesting feature of the migrating neuronal precursors is that they continue to divide during migration30,31 even after they begin expressing neuronal markers.32 This is unlike all other young neurons described in the mammalian CNS.
Mechanism of neuronal migration in the SVZ and RMS Migrating cells in the RMS have an elongated morphology33 with a long leading process. This leading process ends in a growth cone similar to those found at the tip of growing axons. In some cells, a short stubby trailing process is also observed. The majority of the growth cone-containing leading processes in the RMS are oriented in the direction of migration, suggesting that this structure plays an important role for neuronal translocation. Cell adhesion molecules have been suggested to mediate cell–cell interaction during neuronal migration.34 Important clues about the mechanism of migration of olfactory bulb precursors come from studies of the polysialylated neural cell adhesion molecule, PSA-NCAM. PSA-NCAM has multiple homopolymers of alpha-2-8 linked sialic acid (PSA) that make up as much as 30% of the weight of the molecule. This heavy glycosylation is thought to reduce cell adhesion,35 perhaps facilitating cell movements during histogenesis and morphogenesis. Consistent with this view, PSA-NCAM, also known as embryonic NCAM, is highly expressed during embryonic development. However, PSA-NCAM is also expressed in the juvenile and adult brain at sites thought to undergo plastic changes.36,37 Staining with antibodies that recognize PSA-NCAM demonstrate
Figure 2. Chains of migrating neuronal precursors destined for the olfactory bulb reveal a novel form of neuronal migration. (A) Migrating young neurons are organized as chains as revealed by PSA-NCAM immunostaining. This micrograph shows part of the extensive network of chains present in the lateral wall of the lateral ventricle in adult mice.28 (B) Schematic representation of a chain of migrating neuroblasts. During chain migration, neuroblasts (in gray) migrate closely associated to each other without radial glia or axonal guides. These chains of migrating cells are ensheathed by the cell bodies and processes of glial cells (in black) that form a tube-like structure.
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A. Alvarez-Buylla Chain migration represents a novel form of neuronal movement in which no radial glia or axonal processes are used. Instead, cells migrate associated with each other. When cells from the developing cerebral cortex44 or cerebellum,45 which normally migrate along radial glial processes, are grafted into the anterior SVZ, they do not migrate into the RMS. Instead, these cells differentiate close to their site of implantation. This result strengthens the notion that chain migration is a specialized form of neuronal translocation used by specific cell types. It also suggests that the cell surface signals used for radial migration differ from those used for chain migration. The majority of neuronal precursors in the RMS are oriented toward the olfactory bulb, suggesting that directional clues exist along this pathway. The orientation of cells may be due to an endogenous polarization of the migrating cells within the RMS or may be induced by chemoattractive or chemorepulsive gradients. One possibility is that the olfactory bulb secretes an attractant molecule responsible for the directional migration of its precursors. However, this does not appear to be the case; SVZ cells do not orient toward a piece of olfactory bulb in culture,46 and in vivo, olfactory bulb removal does not prevent the forward migration of neuronal precursors (Kirschenbaum and Alvarez-Buylla, unpublished observation). Interestingly, there is recent evidence for a chemorepulsive activity in the caudal septum.46 SVZ explants placed in a collagen gel a short distance from an explant isolated from the caudal septum, show asymmetrical migration, with the majority of the cells migrating from the side of the explant furthest from the septum. A similar chemorepulsive activity on SVZ is demonstrated in the embryonic floor plate of the spinal cord.46 The identity of the repellent substance and a role for a chemorepulsive substances in vivo remains to be demonstrated. It is noteworthy that in the adult brain the majority of precursors come from the wall of the ventricle opposite to the side where the septum is found.29 The function of the glial trabecula surrounding chains of migrating cells in the RMS of adult mice remains unknown. These glial cells could impose a mechanical barrier to prevent migration outside of the RMS. In addition, RMS glia may isolate migrating cells from substances in the surrounding brain parenchyma or could themselves provide factors important for the survival, differentiation or directional movement of the migrating neuroblasts.
cells in the migratory environment may be sufficient to allow movement of the mutant cells. Conversely, transplants of wild-type cells into mutant animals result in absence of migration, highlighting the importance of cell–cell interaction and environment in the migration of these neuronal precursors. It has been shown that enzymatic removal of PSA from NCAM by endosialidase injections into the neonatal anterior forebrain phenocopy the observed migratory defect observed in the NCAM-mutant mice.41 Together, these experiments highlight the importance of the PSA residues for the tangential migration of the olfactory bulb interneuron precursors. Results from the NCAM-mutant mice and the organization of neural precursors as chains, suggest that cell–cell interaction plays an important role in their migration. Chains may correspond to arrays of neuronal precursors following one or multiple guiding processes (e.g. from radial glia or axons that extend along the RMS). However, immunocytochemical and dye labeling experiments have failed to show axonal or radial glial processes in the RMS. Instead the RMS of adult mice is composed of two types of cells:43 type A cells correspond to the migrating neuroblasts, and type B cells that based upon their ultrastructure and high content of glial fibrillary acidic protein (GFAP), are astrocytes. Serial sectioning of the RMS in sagittal and frontal planes and reconstruction of the images reveal an interesting topographical arrangement of type A and B cells (Figure 2C). Chains are formed by the cell bodies and processes of type A cells only. None of the processes of type B cells, or for that matter any other cell type with the exceptions of type A cells, are found inside the chains. Type B cells are more dispersed, but are clearly confined to the RMS. They have multiple branching processes loosely oriented in the direction of migration. The processes of these astrocytes form a tubular trabecula that ensheaths the chains of migrating cells. Therefore, during chain migration, young neurons seem to move closely associated to each other through a ‘tunnel’ formed by the processes of glial cells. Migrating cells establish very close contacts, including small specialized junctions, amongst themselves, but not with the surrounding glia, suggesting that homophilic interaction between migrating cells are critical for this migration. Consistent with this interpretation, small explants of neonatal SVZ grown in culture give rise to chain-like structures.42 Cells in the in-vitro chains migrate away from the explant presumably by association with each other. 210
Chain migration of olfactory bulb interneurons
Perspective
moving tightly apposed to each other forming chains through the juvenile and adult brain. Chain migration, however, is only part of the story behind olfactory bulb interneuron’s continual addition and replacement. Many questions still remain, such as, how is such a long migration established and maintained; why is interneuron replacement in the juvenile and adult brain olfactory bulb necessary; and what is the nature and location of the stem cell population that supports the continual production of interneurons in the adult brain. This and other questions address basic principles of neuronal formation and are likely to reveal novel mechanisms for brain plasticity and brain repair.
Chain migration is a mechanism of movement of neuronal precursors based upon homotypic interactions that require no axonal or radial glia tracks. This form of migration is used in the postnatal brain by cells moving in the tangential plane. Tangential neuronal migration has also been demonstrated in the embryo,47-51 but the corresponding mechanism of cell movement is not known. Chain migration may be used by neural precursors in the developing brain and could explain certain forms of tangential dispersal. In order to determine how widespread chain migration is in the embryonic and adult brain, markers that are specifically related to chain migration need to be identified. In addition to PSA-NCAM, studies have shown that the RMS is rich in other molecules, including extracellular matrix components and glycoproteins such as tenascin, chodriotin sulfate, CD24 and 9-O-acetylated gangliosides.52-54 However, no marker exclusive to chain migration is currently available. The challenge ahead is to determine the nature of the homophilic interactions between migrating young neurons and the precise role of PSA-NCAM during chain migration. In addition to the identification of molecules related to chain migration, techniques to genetically manipulate the neuronal precursors in the SVZ are required. Recent evidence suggests that adenovirus may provide an efficient means of introducing genes into cells in the SVZ.55 This will allow direct testing of the role of different genes in the migration and differentiation of these cells. In addition to a molecular approach and in order to determine how cells actually move during chain migration, new in-vitro and in-vivo techniques are needed to visualize the behavior of neuroblasts in chains. The SVZ and the migratory pathway to the olfactory bulb in the juvenile and adult brain offer a unique system with which to study neuronal migration. Unlike the embryonic brain, the postnatal CNS is more accessible for experimental manipulation; cell migration is not distorted by major morphogenetic displacements, and neuronal production occurs over a long period of time. These properties make the SVZ and the pathway to the olfactory bulb very attractive systems with which to study the mechanism of neuronal movement and guidance, as well as the mechanism of neuronal differentiation. Studies on the origins of olfactory bulb interneurons thus reveal a remarkable traffic of cells,
Acknowledgement I am grateful to Joanne Conover and Daniel Lim for their suggestions on the manuscript. Work was supported by grant NS32116 from the NICHD of the NIH.
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