Directions in Cell Migration Along the Rostral Migratory Stream: The Pathway for Migration in the Brain

doi:10.1016/S0070-2153(04)61006-4

Current Topics in Developmental Biology

Volume 61, 2004, Pages 135-152

https://doi.org/10.1016/S0070-2153(04)61006-4 Get rights and content

Abstract

The rostral migratory stream (RMS) is an extension of the subventricular zone (SVZ) that ends at the center of the olfactory bulb. In rodents, the SVZ and RMS contain the precursor cells for the olfactory interneurons. In development and throughout adult life, these neural precursors leave the SVZ, migrate tangentially along the RMS to the olfactory bulb, from where they then begin to migrate radially to their final destination and differentiate into mature neurons. Live imaging techniques have revealed the nature of RMS migrations at high spatial and temporal resolution. Through the use of genetic and other interventions, the molecular mechanisms controlling the migration are now beginning to emerge. Here we review the nature of the migrations and the putative molecular players.

Introduction

The highly organized laminar structures and nuclei that characterize the adult vertebrate brain result from the orchestrated proliferation, differentiation, and migration of neuronal precursors. Of these steps, migration is critical, because perturbed migration results in congenital brain anomalies such as lissencephally (smooth brain), epilepsy, and mental retardation (Jones et al., 1980). In general, migration of neural precursor cells in mammals occurs during embryonic stages; however, in some regions, it continues in the postnatal brain. In the cerebellum, for example, external granule cells, which are precursors for granule neurons, migrate during lactation from the layer beneath the pia mater deeper into the cerebellum to form the granular layer. These granule cell precursors are guided by radially oriented astrocytes processes, cells often called radial glia (Rakic, 1971). This type of migration is called radial migration. Because this migration occurs postnatally, neuronal circuits in the cerebellum are not yet established at birth, and thus newborns neither walk nor move coordinately, sometimes showing an uncoordinated trembling resembling cerebellar ataxia.

The forebrain including the olfactory bulb is another location that shows postnatal migration. In contrast to the cerebellum, the migration of neuronal precursors in this region is temporally continuous and occurs in both the embryo and adult. Historically, the subventricular zone (SVZ), surrounding the lateral ventricle, and its extension from the anterior part of SVZ (SVZa) to the olfactory bulb has been recognized as a special region showing a high accumulation of mitotic cells in adult mammals (Allen 1912, Bryans 1959, Messier 1958, Smart 1961). By thymidine-H³-labeling, it was shown that the cells in the SVZ migrate along a route termed the rostral migratory stream (RMS), from the SVZa to the center of the olfactory bulb (Fig. 1A–D; Altman, 1969). Together, the subsequent migration from the center to the periphery of the olfactory bulb and the distribution of thymidine-H³-labeled cells in the internal granular and the periglomerular layers suggested that the migrating cells are precursors of granular and periglomerular neurons. Convincing evidence that RMS-migrating cells differentiate into two classes of interneurons, granular and periglomerular cells, but not glia was shown by labeling the migrating cells and their progenitors by using a retrovirus expressing lacZ, which fills the entire cell from the soma to the tip of dendrite (Luskin, 1993).

Thus, throughout life, granule and periglomerular precursor cells originate in the SVZ and migrate to the olfactory bulb along the SVZa and the RMS. This migration differs from the radial migration guided by radial glia fibers seen in the cerebellum, for example. In contrast, the migration, termed a tangential migration, is parallel to the surface of the brain and glia-independent. In addition, after reaching the olfactory bulb, the cells change their direction, migrate peripherally, and then differentiate to two classes of interneurons, granule cells and periglomerular cells (Fig. 1E and F).

Here, we review our current understanding of the molecular mechanisms that drive and guide the tangential migration along the RMS cells as well as the mechanisms of radial migration that leads to their neuronal maturation. In contrast to radial migrations (Hatten, 1999), relatively little is known about tangential migrations, which form the focus of the review.

Section snippets

The Nature of Migration in the Rostral Migratory Stream

Figure 1A shows a sagittal view of the RMS from the forebrain of a postnatal day 0 (P0) mouse stained by cresyl violet. Each precursor cell shows a long leading process followed by a small soma. This morphology is typical of these migrating cells when visualized by DiI labeling (Fig. 1D) or Golgi silver staining (Kishi, 1987). Unlike radial migrations, which are guided by glia (Rakic, 1990), RMS cells are associated with neither glial nor axonal fibers (Kishi et al., 1990). Instead, there is

PSA-N-CAM in Chain Migrations

The presence of PSA is a hallmark of RMS cells, especially in the adult rodent, and is important for their migration (Bonfanti 1992, Rougon 1986; Fig. 1C). N-CAM expressed in developing brain is decorated by PSA (Cunningham et al., 1983), but this decoration disappears as the animal develops. It becomes more restricted and is found in structures that include the RMS, the SVZ, and the hippocampus (Bonfanti et al., 1992). N-CAM knockout mice and the enzymatic removal of PSA point to an important

Other Mechanisms Mediating Migration

Although the previous studies support a role for PSA-N-CAM on RMS migration, alterations in migration are only partial in mice with an inactive N-CAM gene (Chazal et al., 2000). Thus, it seems likely that other molecules contribute to the cell–cell interactions that mediate the putative chain migration. In this context, it is revealing that RMS cells are not seen in surrounding tissues such as the septum or corpus callosum. Finally, the cues that lead to cessation of the tangential migration at

Mechanisms for Directional Navigation

The migration of RMS cells is characterized by highly directed movement, with no dispersion into the septum, the corpus callosum, or the cortex. This points to the presence of chemotactic agents; it also suggests that the environment surrounding the RMS prohibits invasion of RMS cells into these surrounding tissues. In adult mice, glia and their processes form a wall of longitudinally arranged canals commonly referred to as ‘glial tubes’ (Peretto et al., 1997), which ensheath the stream of

Regulation of Differentiation into Mature Neurons

Once the RMS cells reach the center of the olfactory bulb, they appear to dissociate, migrate radially to distinct cell layers, and differentiate into either granule or periglomerular cells (Altman 1969, Lois 1994, Luskin 1993). Although this final migration is termed radial, it is unclear whether the cells are guided by radial glial fibers as seen in the cerebellum (Luskin, 1998). On the one hand, glial fibrillary acidic protein (GFAP)-positive radial fibers radiate from the olfactory

Summary

Participation of many molecules for tangential migration of the RMS cells has been revealed; however, molecules for radial migration and their maturation into granule or periglomerular cells are not well understood. The elucidation of the mechanisms involved in the integration of new cells and establishment of a new functional circuit will be required not only for fundamental knowledge of understanding neural plasticity and memory but also for treating neurodegenerative diseases by using neural

Acknowledgements

We thank Dr. G. Rougon for providing the anti-PSA antibody.

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Directions in Cell Migration Along the Rostral Migratory Stream: The Pathway for Migration in the Brain

Abstract

Introduction

Section snippets

The Nature of Migration in the Rostral Migratory Stream

PSA-N-CAM in Chain Migrations

Other Mechanisms Mediating Migration

Mechanisms for Directional Navigation

Regulation of Differentiation into Mature Neurons

Summary

Acknowledgements

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Curr. Biol.

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Brain Res. Bull.

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J. Biol. Chem.

Neuron

The cessation of mitosis in the central nervous system of the albino rat

J. Comp. Neurol.

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J. Comp. Neurol.

Development of the olfactory bulb: Evidence for glia-neuron interactions in glomerular formation

J. Comp. Neurol.

3H-thymidine-radiographic studies of neurogenesis in the rat olfactory bulb

Exp. Brain Res.

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Anat. Rec.

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Lab. Invest.

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Nat. Neurosci.

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Nat. Neurosci.

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Nature

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Proc. Natl. Acad. Sci. USA

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Nature

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Proc. Natl. Acad. Sci. USA

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Proc. Natl. Acad. Sci. USA

GDNF signalling through the Ret receptor tyrosine kinase

Nature

³H-thymidine-radiographic studies of neurogenesis in the rat olfactory bulb