Modes of Migration in the Developing Brain

1.11.3.1 Two Primary Modes of Migration in the Developing CNS

As discussed in the previous section, the cellular mechanisms underlying the migration of neurons are likely to be similar to those in other cell types. Despite these molecular similarities, two different modes of migration are classically distinguished within the developing brain, radial and tangential migration. In a general sense, radial migration refers to neurons that migrate perpendicularly to the surface of the brain. In contrast, tangential migration is defined by neurons that migrate in a direction that is parallel to the surface of the brain (in either the rostrocaudal axis or the dorsoventral axis) and that is therefore perpendicular to radially migrating neurons. Although this subdivision is primarily based on the orientation of migrating neurons in relation to the neural tube coordinates, it also implicitly reflects the dependence of different classes of neurons on substantially distinct substrates for migration, as we discuss in the next section. In any case, the existence of these different modes of migration in the developing CNS does not indicate that the molecular and cellular mechanisms underlying radial and tangential migration are essentially different. In other words, independent of the mode of migration, alternating cycles of polarization and nucleokinesis are common events to any migrating neuron.

Radial migration is the principal mode of migration within the CNS. In a general sense, radial migration allows the transfer of topographic information from the ventricular zone to the underlying mantle, since neurons that are born nearby tend to occupy adjacent positions in the mantle when using radial migration to reach their final destination. This has important consequences for the organization of the brain. First, radial migration is essential to generate and maintain distinct neurogenetic compartments in the developing neural tube, which is ultimately necessary for the establishment of different cytoarchitectonic subdivisions within the brain (Figure 2). That is, different progenitor regions generate distinct structures in the CNS largely because progenitor cell dispersion is restricted in the ventricular zone (Fishell et al., 1993; Lumsden and Krumlauf, 1996) and migrating neurons from different compartments do not intermingle during their migration. Second, the transfer of positional information from the ventricular zone to the mantle of the brains allows the formation of topographically organized projections, which are crucial for the proper function of the brain. For this reason, radial migration is the basic mechanism preserved throughout evolution to segregate neurons in all regions of the CNS.

Radial migration contributes to the formation of both cortical (i.e., laminar, such as the cerebral cortex, hippocampus, or cerebellum) and nuclear structures (e.g., striatum, red nucleus), although the development of laminar structures is perhaps the most remarkable example on how radial migration may contribute to the formation of complex circuits in the brain. Laminar structures are found in the brain of all vertebrates and, although the most sophisticated example is the mammalian isocortex, the optic tectum of amphibians, reptiles, or birds is a prominent antecedent of this structure. In contrast to brain nuclei, laminar structures are organized to segregate complex patterns of afferent and efferent connections. Because of this organizing principle, the formation of cortical-laminar structures requires the perfect synchronization of proliferation, cell fate, and radial migration mechanisms to determine the number of layers, as well as their cell density and arrangement.

In contrast to radial migration, which appears to play a general role in the formation of major subdivision in the brain, tangential migration is thought to increase the complexity of neuronal circuits because it allows neurons born from distinct

Tangential Versus Radial Migration Brain

Figure 2 Radial and tangential migration in the central nervous system. a and b, Radial glial cells provide structural support for radial migration, a process that results in the generation of different nuclei that are topographically organized in relation to their place of origin. b and c, Tangential migration is independent of radial glial processes and therefore does not respect topographical references. As a result, tangential migration produces an increase in the complexity of different nuclei by providing cell types distinct from those that are locally generated.

Figure 2 Radial and tangential migration in the central nervous system. a and b, Radial glial cells provide structural support for radial migration, a process that results in the generation of different nuclei that are topographically organized in relation to their place of origin. b and c, Tangential migration is independent of radial glial processes and therefore does not respect topographical references. As a result, tangential migration produces an increase in the complexity of different nuclei by providing cell types distinct from those that are locally generated.

ventricular zones to intermingle and occupy a final common destination (Marin and Rubenstein, 2001) (Figure 2). Tangential migration is likely to be a relatively modern mechanism compared to radial migration, but may have been successfully maintained during evolution because it inherently adds complexity to brain circuits through the incorporation of new cell types with those already present in each region (Figure 2).

Compared to radial migration, the existence of tangential dispersion of neurons in the developing brain has only begun to receive much attention, so it may give the impression of being a relatively contemporary discovery. During the last 30 years of the past century, the predominant view on brain development was based on the idea that radial migration was the sole mechanism allowing the movement of neurons from the progenitor regions to their final destination (Rakic, 1990). This idea was consistent with the basic notion of developmental segmentation in the brain because, as discussed earlier, radial migration contributes to the establishment of segregated cytoarchitectonic regions (Lumsden and Keynes, 1989; Puelles and Rubenstein, 1993). Nevertheless, it was clear from early studies using Golgi-stained sections or electron microscopy that some neurons within the developing brain are oriented tangentially in directions inconsistent with radial migration (Stensaas, 1967; Morest, 1970; Shoukimas and Hinds, 1978). Since then, tangential dispersion has been observed in virtually every subdivision of the developing CNS, from the spinal cord and hindbrain (Bourrat and Sotelo, 1988; Ono and Kawamura, 1989; Leber et al., 1990; Marin and Puelles, 1995; Phelps etal., 1996) to the telencephalon (Austin and Cepko, 1990; Halliday and Cepko, 1992; Walsh and Cepko, 1992; O'Rourke etal., 1992,1995; Tan and Breen, 1993; De Carlos et al., 1996). In the case of the cerebral cortex, the most compelling experimental evidence supporting the existence of two general modes of cell dispersion, radial and tangential, came from analysis of clonally related cells using retroviral-mediated transfer or highly unbalanced chimeras (Walsh and Cepko, 1992; Tan and Breen, 1993), unequivocally demonstrated by pioneer time-lapse studies (O'Rourke et al., 1992). The main conclusion from all these studies confirms a general principle in our view of brain development: the organization of distinct cytoarchitectonic regions in the CNS most frequently depends on two mechanisms of cell allocation: radial mosaicism and tangential migration.

The existence of two basic modes of migration within the CNS may lead to the erroneous conclusion that there are two major populations of neurons in the developing brain: those that migrate radially and those that use tangential migration to reach their final destination. Indeed, radial and tangential migrations are just two different mechanisms of cell dispersion that the same population of neurons may use indistinctly to reach their final position within the brain. The stereotyped behavior of the facial bran-chiomotor (fbm) neurons in the hindbrain perfectly illustrates this point (Figure 3). In the mouse, fbm

Ventral midline

hindbrain showing the migration of fbm neurons (red circles) during mouse development. At embryonic (E) day 11.5 (E11.5), fbm neurons migrate tangentially (in the caudal direction) from r4, where they originated, to r6. Later, they migrate tangentially within r6, from ventral to dorsal. Finally, they adopt a radial mode of migration to finally form the facial motor nucleus laterally (nVII).

hindbrain showing the migration of fbm neurons (red circles) during mouse development. At embryonic (E) day 11.5 (E11.5), fbm neurons migrate tangentially (in the caudal direction) from r4, where they originated, to r6. Later, they migrate tangentially within r6, from ventral to dorsal. Finally, they adopt a radial mode of migration to finally form the facial motor nucleus laterally (nVII).

neurons are born in the basal plate of rhombomere 4 (r4), but they finally come to reside in r6. To reach their destination, fbm neurons first migrate tangentially in the caudal direction until they reach r6. Then, they turn 90° and migrate tangentially in the dorsal direction toward the alar-basal boundary. Finally, they turn 90° again and migrate radially toward the pial surface, where they settle to form the facial motor nucleus (for references, see Garel et al., 2000). Similar examples of switching migratory behaviors are present throughout the CNS (cerebellar granule cells, olfactory bulb, and cerebral cortex interneurons, etc.), suggesting that this is a general trend during development. In summary, the same population of neurons may use radial and tangential migration strategies to reach their final destination, likely depending on the extracellular environment available for their dispersion.

1.11.3.2 Evolutionary Advantages of Different Modes of Migration

The development of the cerebral cortex nicely illustrates how the different modes of neuronal migration contribute to the formation of complex circuits in the CNS. The cortex contains two main classes of neurons, the glutamatergic pyramidal neurons and the 7-aminobutyric acid (GABA)-containing neurons. Both classes of neurons use largely different modes of migration to reach their final position in the cortex during development (reviewed in Corbin et al., 2001; Marin and Rubenstein, 2001). Thus, pyramidal neurons migrate radially from the progenitor zones of the pallium to their final position in the cortex. In contrast, interneurons are largely born in progenitor regions of the subpallium and therefore have to migrate tangen-tially to reach the pallium. Once in the pallium, interneurons change their mode of migration from tangential to radial to reach their final destination in the cortex. Thus, projection neurons and interneur-ons use different modes of migration to arrive at the cerebral cortex largely because they derive from segregated progenitors within the telencephalon.

What advantage might there be in producing different classes of neurons at distant places in the CNS instead of producing all of them locally for each brain structure? This question might be answered if we consider that cell patterning and migration are intimately linked during the development of the CNS throughout evolution. In the telencephalon, for example, early dorsoventral patterning specifies distinct domains that produce neurons synthesizing different classes of neurotransmitters (reviewed in Wilson and Rubenstein, 2000; Campbell, 2003). Thus, the dorsal region of the telencephalon - the pallium - becomes patterned to produce glutama-tergic neurons, whereas the subpallium is specified to generate GABAergic and cholinergic neurons. This organization is a primitive trend of the telence-phalon in vertebrates, since it seems to be present in the different classes of living vertebrates (Puelles et al., 2000; Frowein et al., 2002; Gonzalez et al., 2002; Brox et al., 2003) and appears to represent an efficient way to pattern neural progenitors to produce different classes of neurons using a limited number of morphogenetic centers. Thus, patterning mechanisms that have been preserved throughout evolution appear to limit to some extent the generation of multiple classes of neurons in the exact same region of the brain, at least from the perspective of the neurotransmitter phenotype, and tangential migration may have evolved, among other things, to overcome this limitation.

In mammals, the balance between excitatory (glu-tamatergic) and inhibitory (GABAergic) synaptic activity is critical for the normal functioning of the cerebral cortex. As a result, inherited disruption of this balance leads to important behavioral dysfunction in animal models (Liu et al., 2000; Steinlein and Noebels, 2000; Powell et al., 2003) and in severe neurological disorders in humans (Keverne, 1999; Lewis, 2000; Sanacora et al., 2000; Holmes and Ben-Ari, 2001). In that context, the introduction of GABAergic interneurons from an external source to the population of cortical neurons may have played a pivotal role in shaping up neural circuits during the expansion of the cerebral cortex through evolution. A recent study by Lopez-Bendito et al. (2006) has strongly suggested the convergence of these phenomena in the development of the thalamocortical system. This study has demonstrated the existence of a new tangential migration of GABAergic cells within the ventral telencephalon that mediates the navigation of thalamic axons toward their final destination in the neocortex. Specifically, tangential migration from an evolutionarily primitive intermediate target, the stria-tum, contributes to form a permissive bridge for the extension of thalamocortical axons through nonper-missive regions of the ventral telencephalon. In a more general sense, whereas radial migration has been preserved as the mechanism conferring regional identity to distinct structures in the CNS, tangential migration may represent a paradigm to increase the complexity of neuronal circuits during evolution. For instance, the casual incorporation of a migratory route that brings a new population of neurons into an established structure (e.g., through a mutation that induces the expression of a receptor for a guidance molecule in that specific population of neurons) may lead to a complete dysfunctional brain or, occasionally, to a modification of the normal function of the structure representing a competitive evolutionary advantage for the species. Such a mechanism may explain, for example, the differences observed in the number of GABAergic interneurons in the dorsal thalamus of primates - in particular humans - compared to other vertebrates (Letinic and Rakic, 2001). Moreover, the identification of a neocortical origin for a population of GABAergic neurons in the developing human cortex reinforces the existence of such evolutionary trend (Letinic et al., 2002).

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