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aBrunstrom etat. (1997); Polleux etat. (2002).

bZou et al. (1998); Bagri et al. (2002); Stumm et al. (2003).

cConover etat. (2000).

dBehar etat. (1996, 2000); Lopez-Bendito etat. (2003); Lujan etat. (2005). eHirai etat. (1999). 'Pozas and Ibanez (2005). gPowell etat. (2001).

hBloch-Gallego etat. (1999); Yee etat. (1999); Alcantara etat. (2000); Hamasaki etat. (2001). 'Anton etat. (2004); Flames etat. (2004). jMarin etat. (2001); Tamamaki etat. (2003). ^Yacubova and Komuro (2002).

Hu (1999); Wu etat. (1999); Zhu etat. (1999); Gilthorpe etat. (2002); Marin etat. (2003).

aBrunstrom etat. (1997); Polleux etat. (2002).

bZou et al. (1998); Bagri et al. (2002); Stumm et al. (2003).

cConover etat. (2000).

dBehar etat. (1996, 2000); Lopez-Bendito etat. (2003); Lujan etat. (2005). eHirai etat. (1999). 'Pozas and Ibanez (2005). gPowell etat. (2001).

hBloch-Gallego etat. (1999); Yee etat. (1999); Alcantara etat. (2000); Hamasaki etat. (2001). 'Anton etat. (2004); Flames etat. (2004). jMarin etat. (2001); Tamamaki etat. (2003). ^Yacubova and Komuro (2002).

Hu (1999); Wu etat. (1999); Zhu etat. (1999); Gilthorpe etat. (2002); Marin etat. (2003).

tend to migrate superficial to the striatal mantle. However, as development proceeds and the dorsal striatum becomes a large structure in the basal ganglia, cortical interneurons migrate preferentially deep to the striatal mantle (i.e., through the interface between the SVZ of the lateral ganglionic eminence and the striatal mantle). Fourth, interneurons cross the subpallial-pallial boundary, invading the pallium through highly stereotyped routes of migrating, which include the marginal zone, the subplate, and the cortical SVZ. And fifth, interneurons invade the cortical plate and integrate in their appropriate layer according to their birth date. Thus, the migration of cortical interneurons is a complex and well-orchestrated event in the developing forebrain. So, what are the molecular cues that regulate each of these decisions?

Cortical interneurons initiate their movement and engage in long-distance migration probably because they respond to motogenic/scatter factors along their pathway. Several such factors have been identified in the past few years, all of which have in common their ability to also influence the maturation and final differentiation of cortical interneurons. Thus, the neurotrophins BDNF and neurotrophin-4, the scattered factor/hepatocyte growth factor, and the glial-derived neurotrophic factor (GDNF) all have the ability to promote inter-neuron migration to the cortex (Powell et al., 2001; Polleux et al., 2002; Pozas and Ibanez, 2005).

Cortical interneuron migration to the cortex is strongly influenced by molecular activities that prevent interneuron invasion of unsolicited regions. This is the case in the preoptic area and the septum, where the molecular nature of the repulsive activity preventing the migration of interneurons is still unknown (Marin et al., 2003). The striatum constitutes a nonpermissive territory for the migration of cortical interneurons because it expresses class 3 semaphorins (Sema3A and Sema3F) and cortical interneurons express neuropilin receptors for these repellent cues (Marin et al., 2001; Tamamaki et al., 2003).

Cortical interneuron migration is also controlled by permissive and attractive factors that direct inter-neurons in a dorsal direction from the MGE to the cortex (Marin et al., 2003; Wichterle et al., 2003). However, for the first time, a chemoattractive effect on cortical interneurons by a molecule expressed at the cortex has been described. This cue is Neuregulin-1 (NRG1), a member of the neuregulin family of proteins. Of note, different isoforms of NRG1 are differentially expressed in the developing telencephalon, thus controlling distinct aspects of the migration of cortical interneurons (Flames et al., 2004). Thus, membrane-bound forms of NRG1, Cystein-rich domain (CRD)-NRG1, are expressed in the route of interneuron migration from the MGE to the pallial-subpallial boundary, and it seems to create a permissive corridor for interneuron migration toward the cortex. In addition, diffusible forms of NRG1, Ig-NRG1, are specifically expressed in the cortex, from where they appear to attract interneuron migration. Other factors are likely to attract interneuron migration to the cortex. For example, GDNF also acts as an attractive cue for interneuron migration in vitro (Pozas and Ibafiez, 2005), although its wide distribution in the telencephalon suggests that it may rather act as motogenic factor in vivo.

It has been suggested that cortical interneurons may use corticofugal axons as a substrate for their migration to the cortex. Axons have been proposed as substrates for other tangentially migrating cell populations, such as gonadotropin-releasing hormone neurons (Wray, 2002), and in vitro evidence suggests that axons may serve as substrates for the migration of cortical interneurons (McManus et al., 2004a). Moreover, molecules specifically expressed in corticofugal axons appear to influence inter-neuron migration in vitro (Denaxa et al., 2001). At the peak of interneuron migration, however, most cells migrate through axon-poor regions such as the cortical SVZ, suggesting that axons may influence primarily early stages of interneuron migration to the cortex.

The guidance of cortical interneurons may also be influenced by neuronal activity. In agreement with this hypothesis, several studies have described the early expression of GABA and glutamate receptors at the cerebral cortex before the formation of synapses (Metin et al., 2000; Lopez-Bendito et al., 2002a, 2002b; Lujan et al., 2005). The function of some of these receptors has been tested in vitro. For example, stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in slice cultures induces GABA release in tangentially migrating cells (Poluch and Konig, 2002). In contrast, in vitro blockade of GABAB receptors leads to a derailment of GABAergic interneurons within the neocortex (Lopez-Bendito et al., 2003). Others neu-rotransmitter receptors, such as NMDA, AMPA/ Kainate, and GABAA, are also functional on tangen-tially migratory interneurons (Metin et al., 2000; Soria and Valdeolmillos, 2002), suggesting that they also influence the migration cortical interneurons through a yet unknown mechanism.

Once interneurons reach the cortex, they invade the cortical plate and distribute through the different cortical layers. Interestingly, invasion of the cortical plate does not occur automatically as inter-neurons reach the cortex, but rather seems to be a highly stereotyped process designed to allow the homogeneous dispersion of cortical interneurons throughout the whole rostrocaudal and mediolateral extent of the cerebral cortex (G. Lopez-Bendito and O. Marin, unpublished observations). In addition, invasion of the cortical plate by inter-neurons may depend on radial glia (Ang et al., 2003; Lopez-Bendito et al., 2004; Tanaka et al., 2003) and thus on the mechanisms described for cortical pyramidal cells (see Section 1.11.4). Nevertheless, some of the molecules that influence migration of projection neurons, such as Cdk5, do not seem to influence the tangential migration of cortical interneurons or their subsequent movement into the cortical plate (Gilmore and Herrup, 2001).

1.11.5.2 Migration of Facial Branchiomotor Neurons

Tangential cell movements during CNS development are not restricted to forebrain. Indeed, tangential migration is present at all rostrocaudal levels of the neural axis. In the hindbrain, for example, the facial (nVII) branchiomotor neurons of several vertebrates, including fish and mammals, follow a large stereotyped migration that includes tangential migration from their origin in r4 to caudal r6 or r7 (reviewed in Chandrasekhar, 2004). Tangentially migrating fbm neurons use a mode of migration very similar to the somal translocation described in the cortex (Book and Morest, 1990), in which the nucleus moves along a large leading extension as the migrating cell leaves behind an axonal process that reflects the migratory path.

It has been shown that environmental cues present in r5 and r6 mediate fbm neuronal tangential migration. Interestingly, chick fbm neurons undergo limited caudal migration naturally; however, transplantation studies have demonstrated that these cells have the ability to migrate caudally when transplanted into mouse r4, demonstrating that the cues necessary for the initiation, and perhaps maintenance, of caudal migration are absent in the chick hindbrain (Studer, 2001). Additional evidence for environmental cues regulating fbm migration comes from genetic and molecular studies in zebra fish. In the zebra fish mutant trilobite (tri), fbm neurons fail to migrate tangentially into r5-7 (Bingham et al., 2002). This phenotype, however, can be rescued when tri mutant fbm neurons are transplanted into a wild-type environment, whereas wild-type fbm neurons fail to migrate caudally in a mutant context. What molecules are responsible for this behavior? Tangentially migrating fbm neurons regulate the expression of genes encoding the cell membrane proteins, such as TAG-1, Ret, and Cadherin-8, and this regulation is dependent on their location at r4, r5, or r6 (Garel et al., 2000). Interestingly, in embryos deficient for Ebfl or Nkx6-1, fbm neurons either fail to migrate or undergo an incomplete caudal migration, prematurely expressing an abnormal combination of markers (Garel et al., 2000). These data suggest that fbm neurons adapt to their changing environment by switching on and off specific genes.

Finally, studies have shown that tangential migration of fbm neurons is controlled by neuro-pilin receptors, as is the case for cortical interneurons. Thus, loss of Neuropilin-1 (Nrpl) in the mouse compromises the tangential migration of fbm neurons, causing the formation of misshapen and malpositioned facial motor nuclei. In contrast to cortical interneurons, however, which rely on class 3 semaphorins for their guidance, soma migration of fbm neurons relies on the presence of a structurally unrelated Nrp1 ligand, an isoform of vascular endothelial growth factor (VEGF) termed VEGF164 (Schwarz et al., 2004).

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