Transcriptional Regulation of Tangential Neuronal Migration in the Vertebrate Hindbrain

C H A P T E R

21 Transcriptional Regulation of Tangential Neuronal Migration in the Vertebrate Hindbrain T. Di Meglio, F.M. Rijli Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

O U T L I N E 21.1 Introduction 21.2 Breaking Boundaries: Transcriptional Regulation of Tangential Neuronal Migration Across Rhombomeres 21.2.1 Transcriptional Control of FBM Neuron Tangential Migration 21.2.1.1 Providing Positional Identity to FBM Neuron Progenitors: Induction and Maintenance of r4Specific Hox-Dependent Genetic Circuitry 21.2.1.2 Directionality of r4-Derived FBM Neuron Tangential Migration and Hoxb1 Function 21.2.2 Transcriptional Control of Tangential Migration of Rhombic Lip-Derived Neurons 21.2.2.1 TF Expression Defines Distinct RL Progenitor Pools Intersecting along the DV and AP Axes

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21.1 INTRODUCTION The adult hindbrain, or rhombencephalon, is composed of the posteriorly located medulla oblongata, the ventroanteriorly located pons, and the dorsoanteriorly located cerebellum and is densely packed with vital structures. Among these are the nuclei and central targets of the cranial nerves that innervate the muscles of the head and neck; transmit sensory information about hearing, balance, and taste; and control the cardiovascular and gastrointestinal systems (Kandel et al., 2000). Moreover, several specific hindbrain nuclei,

Cellular Migration and Formation of Neuronal Connections: Comprehensive Developmental Neuroscience, Volume 2 http://dx.doi.org/10.1016/B978-0-12-397266-8.00033-8

21.2.2.2 Transcriptional Control of General Properties of RLD Tangential Migration 21.2.2.3 Distinct Responses to Midline Signaling and Directionality of Migration 21.2.2.4 Transcriptional Control of the Directionality of uRL-Derived Granule Cell Migration 21.2.2.5 Transcriptional Control of Directionality of Mossy Fiber lRLDerived Precerebellar Neuron Migration

collectively referred to as the precerebellar system, convey inputs about movement and balance to the cerebellum (Sotelo, 2004). During development, the hindbrain neuroepithelium is organized into neural progenitor domains generated under the coordinated action of different morphogens that intersect along the anteroposterior (AP) or dorsoventral (DV) axes (e.g., retinoic acid, bone morphogenetic proteins (BMPs)) (Jessell, 2000; Lumsden and Krumlauf, 1996). The induction of combinatorial expression codes of distinct classes of transcription factors (TFs) in progenitor cells will in turn instruct newly formed neurons about

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their positional identity and result in the acquisition of specific subtype identities with radial or tangential migratory properties (Hatten, 1999). Although radially migrating neurons remain within the same neuromeric compartment as their progenitor cells, tangentially migrating neurons can cross interneuromeric boundaries along the AP axis and travel over long distances. The early AP organization of the hindbrain neuroepithelium has been conserved throughout vertebrate evolution. The presumptive hindbrain region is partitioned

into a fixed number of neuroepithelial segments known as rhombomeres (r) (Figure 21.1) (Kiecker and Lumsden, 2005). Neural progenitors of distinct rhombomeres remain spatially segregated, and long-term fate mapping studies have revealed that cell progenies of individual rhombomeres form transverse stripes running throughout the ventriculopial axis of the mature hindbrain (Marin and Puelles, 1995; Wingate and Lumsden, 1996). Although at late stages the hindbrain loses its overtly segmental structure, dividing progenitor cells

FIGURE 21.1 Transcriptional control of facial

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branchiomotor motoneuron migration. (a) Schematic representation of the facial branchiomotor (FBM) neuronal migratory route in the developing E12.0 wild-type (WT) hindbrain (ventral view). The dashed lines depict rhombomere (r) boundaries. FBM neurons originate from progenitors in r4 and tangentially migrate, first caudally through r5 and then dorsolaterally in r6 (1, red arrow), where they finally switch to radial migration (2, green arrow) and settle into their final ventral position. While migrating caudally, FBM cell bodies leave behind an axonal process that navigates toward an exit point in r4. (b) Genetic circuit diagram illustrating the molecular mechanisms of transcriptional regulation during the successive phases of FBM neuron migration. Ebf1 activates Tag1 expression, while repressing Cadherin8 (Cad8) expression. Phox2b and Nkx6.1 cooperate to repress Unc5h3 expression. Ret expression is cosilenced by all these TFs and Tbx20. Note that none of these regulatory relationships have been shown so far to be mediated by direct regulation. (c) Phenotype of Phox2bKIPhox2a or Nkx6.1 KO mice. The facial motor nucleus (FMN) is absent from r6. FBM neurons prematurely upregulate Unc5h3 and Ret and shift toward radial migration into r4 and r5. (d) In Ebf1 KO mice, some FBM neurons abnormally downregulate Tag1 and ectopically migrate radially into r5. (e) In Kreisler knockout (KO) embryos that lack the r5 territory, FBM migrating neurons switch to radial migration after the r4 posterior boundary. KI, knock-in; nVII, genu of the facial nerve.

21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES

retain segmental molecular patterning cues throughout development (Lumsden and Krumlauf, 1996; Wingate and Lumsden, 1996). Thus, longitudinal columns of conventional hindbrain nuclei are contributed by neuronal subpopulations of multirhombomeric origin that settle in the nucleus by radial migration, generally respecting their AP order of origin during development (Farago et al., 2006; Oury et al., 2006; Pasqualetti et al., 2007). Nonetheless, certain hindbrain neuronal populations undergo a phase of long-distance tangential migration across several rhombomeres before settling at their final destination. This chapter focuses on two specific populations of hindbrain neurons for which recent data have provided insights about the transcriptional regulation of their tangential migration: the facial branchiomotor (FBM) and precerebellar neurons.

21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES 21.2.1 Transcriptional Control of FBM Neuron Tangential Migration The branchiomotor neurons of the facial (seventh) cranial nerve innervate the muscles of facial expression. In the mouse, FBM neurons are born between embryonic day (E)9.0 and E11.0, ventrally in r4. Between E10.0 and E13.5, they translocate their somata caudally while projecting their axons rostrally through an exit point located in dorsal r4 to target the second branchial arch (Figure 21.1(a); Studer et al., 1996; reviewed in Chandrasekhar, 2004; Cordes, 2001; Guthrie, 2007). r4-Derived FBM neuron somata migrate tangentially in a subventricular position close to the ventral midline through r5 and into r6, where they undertake a short dorsolateral migration away from the basal plate. Then, FBM neurons follow a ventral radial migration step along the glia scaffold to reach their final destination near the pial surface in ventral r6, where they bilaterally condense in a pair of seventh nerve motor nuclei (Figure 21.1(a)). Dorsolateral tangential migrations within the rhombomere of origin also are observed for the r2- and r3-derived trigeminal branchiomotor neurons of the fifth cranial nerve, innervating mastication muscles, as well as for the r5-derived visceral motor neurons of the seventh nerve that innervate the parasympathetic ganglia controlling lacrimal and salivary gland activities. In recent years, significant progress has been made in identifying a genetic cascade of transcriptional regulators and their downstream targets that are intrinsically and extrinsically required to ensure FBM neuron

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tangential migration (reviewed in Chandrasekhar, 2004; Guthrie, 2007). Analysis of different mutant backgrounds has shed light on the role of specific TFs that modulate the responsiveness of FBM neurons to external guiding cues. These studies have found that distinct signaling pathways are involved in the initial tangential and later radial migration of these neurons (Garel et al., 2000; Mu¨ller et al., 2003; Rossel et al., 2005; Schwarz et al., 2004). The initiation of caudal migration from r4 following the specification of FBM progenitors and the later switch to radial migration in r6 are partially achieved through transcriptional cross-regulation between a set of TFs, including Tbx20, Nkx6.1, Phox2a, Phox2b, and Math3/NeuroM, as well as Ebf1, Ebf2, and Ebf3 (Figure 21.1(b); see references below). The expression of the paired-like homeodomain (HD) factor Phox2b generally precedes that of Phox2a in neuronal progenitors and persists in postmitotic neurons. Phox2b is, therefore, likely to act at the interface between regional patterning and neuronal type specification (Pattyn et al., 1997). Phox2b is essential for the specification of cranial motoneurons (Dubreuil et al., 2002; Pattyn et al., 2000). Phox2b and Nkx6.1 are coexpressed in cycling progenitors and postmitotic FBM neurons throughout migration and are involved in a complex cross-regulatory loop implicated in both specification and migration of FBM (Dubreuil et al., 2002; Mu¨ller et al., 2003; Pattyn et al., 2000, 2003a,b). Forced expression of Phox2b induces the activation of Nkx6.1 and its paralog Nkx6.2 in branchiomotor progenitors (Dubreuil et al., 2002). Conversely, Nkx6.1 is not sufficient to induce activation of Phox2b (Pattyn et al., 2003a). However, the maintenance of high levels of Phox2b in ventral r4 through late stages of FBM neuron generation requires the combined regulation of the Nkx6.1 and Nkx6.2 proteins (Figure 21.1(b); Pattyn et al., 2003b). Rescue of Phox2b function in FBM neuron progenitors by gene replacement with its paralog Phox2a revealed an additional role for Phox2b in controlling FBM neuron tangential migration (Coppola et al., 2005). In Phox2bPhox2aKI mutants, FBM neurons stalled in ventral r4/r5 or were found in ectopic dorsal positions within these rhombomeres (Figure 21.1(c)). Similar migratory defects were also observed in single Nkx6.1 mutants (Figure 21.1(c); Mu¨ller et al., 2003; Pattyn et al., 2003b). Thus, while Nkx6.1 is expressed by both progenitors and FBM migrating neurons, it is only required for the caudal migration of these neurons. In early progenitors, Nkx6.1 function is likely rescued by Nkx6.2, which is in turn downregulated in migrating neurons (Mu¨ller et al., 2003). FBM neurons modulate their intrinsic gene expression program during sequential steps of migration. For instance, Tag1, a cell adhesion molecule of the

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immunoglobulin family, is normally expressed throughout caudal migration, but it is switched off during dorsolateral migration in r6. The expression of the Netrin-1 receptor Unc5h3 and Cadherin-8 (Cad8) is instead turned on during the final step of dorsolateral migration in r6 (Figure 21.1(b); Garel et al., 2000; Mu¨ller et al., 2003). In the Phox2bPhox2aKI and Nkx6.1 mutants described above, FBM neurons that do not migrate caudally out of r4 prematurely express Unc5h3 (Mu¨ller et al., 2003). Moreover, inactivation of the basic helix-loop-helix (bHLH) TF Ebf1 results in the failure of FBM neurons to migrate caudally into r6: they undergo a premature dorsolateral migration while still in r5 (Figure 21.1(d); Garel et al., 2000). This defect correlates with a premature downregulation of Tag1 and with the ectopic expression of Cad8 and the GDNF receptor subunit Ret. Ret is normally activated as FBM neurons exit r4 and enter r5 (Figure 21.1(b)). Notably, in all single Nkx6.1, Math3, Ebf1, or Tbx20 mutants, the expression of Ret is prematurely upregulated in FBM neurons in r4 (Garel et al., 2000; Mu¨ller et al., 2003; Ohsawa et al., 2005; Song et al., 2006). Expression analysis further suggested that these TFs may not function in an epistatic genetic cascade, raising the possibility that they might be coregulating similar targets, such as Ret. However, Ret mutants do not show FBM neuron migratory defects (Song et al., 2006), indicating that this gene is either dispensable for migration or functionally redundant with other signaling molecules. Overall, the data suggest that the coordinate activity of these TFs is cellautonomously required by FBM neurons in order to adapt to their changing environment and select an appropriate local migratory pathway. In addition to intrinsic molecular mechanisms, noncell-autonomous mechanisms related to the changing migratory environment can also contribute to the establishment of the stereotyped migratory pattern of FBM neurons. For instance, in Krox20 and kreisler mutants, which lack r5 but maintain r6 territory, FBM neurons prematurely switch on a r6-specific gene combination and migrate dorsolaterally immediately after exiting r4, indicating that the selection of a final territory may be related to changing local instructive cues (Figure 21.1(e); Garel et al., 2000). In this respect, analysis of mouse–chick chimeras indicated that environmental cues embedded in mouse r5 and r6 are directly involved in initiating caudal migration of FBM neurons (Studer, 2001). Guidance systems required for the caudal attraction of FBM neurons include the chemokine SDF1 and its receptor CXCR4 in zebrafish (Sape`de et al., 2005) as an isoform of the vascular endothelial growth factor (VEGF164) and its receptor neuropilin 1 in mouse (Schwarz et al., 2004). In VEGF164 mutants, despite defects in tangential migration, the radial migration of FBM neurons is preserved, suggesting that other signals

are responsible for this migratory process. The final radial migratory step relies on reelin-dependent signaling. Accordingly, Reeler mutant mice exhibit defects in the radial pattern of FBM cell movement, but the tangential path of soma migration is intact (Rossel et al., 2005). 21.2.1.1 Providing Positional Identity to FBM Neuron Progenitors: Induction and Maintenance of r4-Specific Hox-Dependent Genetic Circuitry The TFs described above regulate the timely expression of effectors required for the tangential migration of FBM neurons. Nevertheless, all such TFs are at least partially expressed by other motoneurons; thus, it is unlikely that they alone are sufficient to promote the caudal directionality of r4-derived FBM neuron migration, rather than regulating general aspects of neuronal differentiation and tangential migration. On the other hand, the Hox family of homeoboxcontaining genes plays an early role in conferring segmental identity and early patterning information to rhombomere neuroepithelial compartments and their derivatives (reviewed in Glover et al., 2006; Lumsden and Krumlauf, 1996; Rijli et al., 1998). Hox gene transcripts are also present at later developmental stages of hindbrain development in selected populations of progenitors and differentiating postmitotic neurons (e.g., Davenne et al., 1999; Gaufo et al., 2000; Gavalas et al., 2003). Thus, in addition to their early roles, Hox genes may be critically involved in the establishment of stereotyped neuronal migratory behavior and spatially restricted patterns of connectivity along the hindbrain AP axis (e.g., Cooper et al., 2003; Geisen et al., 2008; McClintock et al., 2002; Oury et al., 2006; see below). A number of studies have shown that auto- and cross-regulatory interactions among Hox genes contribute to the establishment and maintenance of their segmental expression patterns in neural progenitors (Figure 21.2(a); Gould et al., 1998; Maconochie et al., 1997; Manzanares et al., 2001; Popperl et al., 1995). A clear case of this is the hierarchy of cross-regulatory interactions that controls r4 segmental identity and the development of FBM neuron progenitors (Figure 21.2(b); see below). At presegmentation stages, Hoxa1 and Hoxb1 expression is directly induced in the neuroepithelium of the presumptive hindbrain by retinoic acid, the main vitamin A derivative that diffuses from presomitic and somitic mesoderm. Retinoic acid acts through activation of specific nuclear receptors that bind to specific retinoic acid response elements at the Hoxa1 and Hoxb1 loci (Dupe et al., 1997; Frasch et al., 1995; Glover, 2001; Glover et al., 2006; Marshall et al., 1994; Studer et al., 1996). Hoxa1 in turn also participates into Hoxb1 transactivation in cooperation with specific

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FIGURE 21.2 Positional specification of r4 FBM neuron progenitors. (a) Drawing illustrating the anteroposterior (AP)-nested expression domains of Hox paralog group 1 (PG1), PG2, and PG3 gene expression in the developing hindbrain neuroepithelium. r4 FBM neuron progenitors express Hox PG1 (Hoxa1, Hoxb1) and PG2 (Hoxa2, Hoxb2) but not PG3 (Hoxa3, Hoxb3, Hoxd3) genes. Part of such transcriptional code (see main text) is also maintained into postmitotic migrating FBM neurons (gray arrow). (b) Circuit diagram illustrating the transcriptional interactions involved in the specification of r4 FBM neuron progenitors. Hoxa1 and Hoxb1 are initially activated in neural tissue by retinoic acid. While Hoxa1 also participate in Hoxb1 activation, it is in turn rapidly downregulated. Subsequent Hoxb1 maintenance in r4 is dependent on autoregulation. Hoxb1 directly upregulates Hoxb2 in r4, and Hoxb2 may feedback on Hoxb1 expression to reinforce its late maintenance (dashed line). Late maintenance of Phox2b expression is essential for r4 FBM progenitor identity and may be directly regulated by Hoxb1 and/or Hoxb2. Late Phox2b regulation by Nkx6.1 and Nkx6.2 could indirectly be achieved through their contribution to Hoxb1 expression maintenance. Furthermore, Nkx2.2 appears to enhance Hox-mediated transactivation of Phox2b expression.

cofactors, such as Pbx (Di Rocco et al., 1997, 2001). While Hoxa1 is subsequently downregulated, maintenance of Hoxb1 expression in r4 is dependent on a conserved autoregulatory enhancer element (b1-ARE) (Popperl et al., 1995). In r4, Hoxb1 further upregulates Hoxb2 expression through cooperative binding with Pbx of a Hoxb2 r4-specific enhancer (Ferretti et al., 2005; Jacobs et al., 1999; Maconochie et al., 1997). Moreover, Hoxb2 may also feedback on Hoxb1 expression levels in r4 (Davenne et al., 1999; Pattyn et al., 2003b). In addition, Hoxb1 can regulate Hoxa2 expression levels in r4 via a conserved crossregulatory mechanism, adding a supplementary component to the gene regulatory network for r4 (Tumpel et al., 2007). Finally, while early restriction of Hoxb1 to r4 is dependent on retinoic-acid-mediated repression in r3 and r5 (Studer et al., 1994), maintenance of such repression may be mediated by Hox paralog group 3 genes (Gaufo et al., 2003). Hoxb1 is needed to specify r4 identity and to induce the appearance of FBM neuron progenitors. On the one hand, Hoxb1 inactivation in the mouse triggers early patterning changes of r4 into r2-like identity, such that ventral r4 progenitors take on a dorsolateral migratory pathway in a manner similar to trigeminal branchiomotor neurons (Gaufo et al., 2000; Goddard et al., 1996; McClintock et al., 2002; Studer et al., 1996). Moreover, late downregulation of Hoxb1 in ventral r4 FBM neuron progenitors, as observed in Nkx6.1/6.2 compound mutants, instead induces a switch to serotonergic neuron

identity, a phenotype also observed in Hoxb2-mutant mice (Pattyn et al., 2003b). On the other hand, the ectopic expression of Hoxb1 is sufficient by itself to confer FBM neuron identity to ectopic ventral progenitor cells and to change the migratory properties of their progeny (Bell et al., 1999; Gaufo et al., 2003; Jungbluth et al., 1999). Several studies identified Phox2b and Nkx6.1 as key members of a hierarchy of Hox-regulated genes involved in FBM neuron specification, migration, and axon connectivity (Coppola et al., 2005; Dasen et al., 2003; De Marco Garcia and Jessell, 2008; Samad et al., 2004; see references above). Indeed, the temporally extended specification of FBM progenitors in ventral r4 depends on the maintenance of Phox2b expression, which requires combined regulation by Nkx6.1 and Nkx6.2 proteins. Moreover, Nkx6-mediated regulation is indirectly achieved through Hoxb1 function (Pattyn et al., 2003b). In this respect, Hoxb1 and Hoxb2 act as direct transcriptional regulators of Phox2b in FBM neuron progenitors, in cooperation with Pbx and Prep/Meis cofactors (Figure 21.2(b); Samad et al., 2004). 21.2.1.2 Directionality of r4-Derived FBM Neuron Tangential Migration and Hoxb1 Function In both mouse and zebrafish embryos, Hoxb1 transcript and protein are additionally maintained at low levels within FBM neurons during their migration (Goddard et al., 1996; McClintock et al., 2002). Thus,

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FBM neurons maintain their r4-specific Hox molecular address while migrating through r5–r6, which are devoid of Hoxb1 expression at the stage of migration. Such a late expression in FBM neurons supports the idea that Hoxb1 controls the temporally extended generation of FBM neurons (see above) and strongly suggests that it may also have a direct role in controlling the directionality of their migration. Several observations indirectly support this idea. First, Hoxb1 null mice display a severe facial paralysis (Goddard et al., 1996; Studer et al., 1996) and morpholino-antisense-mediated downregulation of its zebrafish ortholog Hoxb1a (McClintock et al., 2002) prevented the posterior migration of FBM neurons. Second, Hoxb1-deficient FBM neurons still normally target the second branchial arch, indicating that they may not have acquired a full r2-like trigeminal identity (Goddard et al., 1996; McClintock et al., 2002; Studer et al., 1996; see above). Third, analysis of a Hoxb2-mutant allele in which Hoxb1 is progressively downregulated after E11.5 provides evidence of a late requirement for Hoxb1 in the generation of a sizeable population of caudally migrating FBM neurons (Davenne et al., 1999; Pattyn et al., 2003b; see above). Finally, cell transplantation experiments in zebrafish have shown that hoxb1a and its HD cofactor lazarus (lzr)/pbx4 are mainly required cell-autonomously to control FBM neuron migration; however, partial non-cell-autonomous effects were also observed, indicating additional roles of hoxb1a/pbx4 in the early patterning of the r5–r6 environment through which FBM neurons migrate (Cooper et al., 2003). Further supporting the potential involvement of Hoxb1 within migrating neurons, a microarray screening in zebrafish comparing normal versus hoxb1a-deficient r4 tissue identified an array of downstream targets including prickle1b (Rohrschneider et al., 2007). Prickle (pk) genes are components of the planar cell polarity (PCP) pathway implicated in the noncanonical Wingless/Wnt signaling known to control cell polarity in Drosophila and cell movements, including gastrulationassociated and neuronal migrations in vertebrates (reviewed in Chandrasekhar, 2004; Goodrich, 2008; Park and Moon, 2002; Tree et al., 2002; Veeman et al., 2003). Prickle1 is expressed both within the FBM neurons and in their local environment and mediate their caudal migration (Bingham et al., 2010; Carreira-Barbosa et al., 2003). Morpholino-antisense-mediated downregulation coupled with a cell transplantation approach confirmed that zebrafish prickle1b is cell-autonomously required within facial neurons to control their migration and that its expression is hoxb1a-dependent (Rohrschneider et al., 2007). Additional genetic screens in zebrafish and mice revealed that several other PCP genes are involved in orienting FBM neurons during tangential migration (Bingham et al., 2010; Carreira-Barbosa et al., 2003;

Jessen et al., 2002; Nambiar et al., 2007; Song et al., 2006; Vivancos et al., 2009; Wada et al., 2006). Finally, another microarray screening in the mouse (Tvrdik and Capecchi, 2006) has identified a few additional Hoxb1 downstream targets genes that are involved in FBM neuron migration and positioning of the facial nucleus. These include two genes that were concomitantly identified in the zebrafish microarray screening, namely, the serine/threonine cyclin-dependent kinase 5/p35 that is involved in the general machinery for FBM neuronal migration (Ohshima et al., 2002) and the cadherin EGF LAG seven-pass G-type receptor 2, another member of the PCP pathway. Altogether, the above data strongly support the idea that Hox genes are part of a network of TFs and signaling molecules that regulates specification and directional migration of FBM neurons. In particular, Hoxb1 plays a prominent role, being expressed in r4-derived FBM progenitors and differentiating neurons. One possibility is that the continued expression of Hoxb1 during FBM neuron specification and migration is responsible for a context-dependent modulation of the activity of downstream genes and signaling molecules resulting in the selection of a specific directionality of migration. In the following sections, the authors make an additional case for such a context, taking into consideration another population of tangentially migrating neurons in the developing hindbrain, the precerebellar pontine neurons (PN).

21.2.2 Transcriptional Control of Tangential Migration of Rhombic Lip-Derived Neurons The rhombic lip (rautenlippe, RL) forms a stripe of germinative neuroepithelium at the interface of the dorsal alar plate and the nonneuronal roof plate. The RL rims the opening of the fourth ventricle along the entire AP axis of the developing hindbrain. The RL gives rise to a defined rostrocaudal sequence of tangentially migrating cell populations, fated to become neurons of the cerebellar, cochlear, and precerebellar systems, as well as nonneuronal structures (Figures 21.3 and 21.4; Altman and Bayer, 1987a; Ellenberger et al., 1969; Farago et al., 2006; Hunter and Dymecki, 2007; Landsberg et al., 2005; Nichols and Bruce, 2006; Pierce, 1966; Ray and Dymecki, 2009; Rodriguez and Dymecki, 2000; Sotelo, 2004; Wingate, 2001; Wingate and Hatten, 1999). In recent years, developmentally important TFs whose expression partitions the RL neuroepithelium into molecular subdomains of progenitors along both the DV and the AP axes, relevant to later neuronal identity and migratory properties of their lineages, have been identified.

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21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES

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FIGURE 21.3 Fate mapping of rhombic lip (RL) derivatives. Diagrams representing dorsal and sagittal views, respectively, of (a) early and (b) late stages of mouse hindbrain. The most dorsal domain of the neuroepithelium corresponds to the RL, which is divided into the nonneuronal (a, orange) and neuronal (a, red) RLs. Ventral to the RL lies the dorsal ventricular zone (VZ) (a, green). The nonneuronal RL gives rise to the roof plate (a, gray) and later the choroid plexus (b, gray). The identity and final location of neuronal RL derivatives (b) depends on their origin along the AP axis. R1 RL is referred as the cerebellar upper RL (uRL) (a, yellow), while the lower RL (lRL) is subdivided in the auditory RL from r2 to r5 (a, purple) and the precerebellar lRL from r6 to r8 (a, blue). The uRL generates progenitors of all cerebellar glutamatergic neurons (b, yellow), including projection neurons of the deep cerebellar nuclei (DCN), unipolar brush cells that migrate into the molecular layer (ML), and granule neuron progenitors, that migrate tangentially into the external granule cell layer (EGL) before exiting the cell cycle and turning radially (arrows in b) to reach the inside of granule cell layer (IGL). The auditory lRL generates several neuronal subpopulations of the cochlear nuclei (b, purple) that are also contributed from dorsal VZ progenitors (a). The precerebellar lRL is the source of the mossy fiber precerebellar nuclei (b, light blue) including neurons of the pontine gray nucleus (PGN), the reticulotegmental nucleus (RTN), the lateral reticular nucleus (LRN), and the external cuneate nucleus (ECN). Neurons forming the inferior olivary nucleus (ION, dark blue in b) originate from the ventral neuronal lRL (a, red–green striped or dark blue color codes).

21.2.2.1 TF Expression Defines Distinct RL Progenitor Pools Intersecting along the DV and AP Axes Starting at E8.0 in the mouse, RL progenitors become distinguished from the adjacent ventricular zone by the activation of Wnt1 expression (Figure 21.4). Fate mapping analysis showed that the Wnt1þ RL progeny gives rise to all known RL tangentially migrating neuronal derivatives (Figure 21.3; Farago et al., 2006; Landsberg et al., 2005; Nichols and Bruce, 2006; Rodriguez and Dymecki, 2000). Moreover, lineage analysis led to the discovery of Wnt1þ RL nonneuronal derivatives. Indeed, roof plate and choroid plexus progenitors lie within the most dorsal Wnt1þ RL domain (Figure 21.3; Hunter and Dymecki, 2007). Morphogens secreted at the roof plate and choroid plexus levels in turn induce neuronal RL specification and contribute to hindbrain morphogenesis (Bitgood and McMahon, 1995; Chizhikov et al., 2006; Currle et al., 2005; Emerich et al., 2005; Huang et al., 2009; Hunter and Dymecki, 2007; Redzic et al., 2005; see below). Thus, the Wnt1 expression domain operationally defines the entire DV extent of the RL

neuroepithelium (Bally-Cuif et al., 1992; Parr et al., 1993; Ray and Dymecki, 2009). Inside of this domain, each of the neuronal and nonneuronal lineages emerges from distinct DV molecularly defined pools that specifically express TFs such as Lmx1a, Math1, Ngn1, Mash1, or Pft1a and that are predictive of cell fate. Such DV domains also intersect with spatially restricted AP domains, delimited by nested Hox gene expression patterns (Figure 21.2(a); see below), that define three main RL rostrocaudal domains (Figure 21.3). The rostral or upper RL (uRL) forms in r1, is devoid of Hox gene expression, and gives rise to the cerebellar derivatives (Wingate, 2005; Wingate and Hatten, 1999; see below). The caudal or lower RL (lRL) spans from r2 to r8, each expressing distinct Hox codes (Narita and Rijli, 2009), and comprises the auditory (r2–r5) and precerebellar (r6–r8) domains, contributing, respectively, to the cochlear complex and precerebellar nuclei that extend climbing and mossy fibers to the cerebellum (Farago et al., 2006; Ray and Dymecki, 2009). Position along the AP axis of RL-derived cells in turn defines their stereotyped tangential migratory pathways (see below).

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Midline

1: uRL (sagittal)

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FIGURE 21.4

Dorsoventral regionalization of RL by transcription factor expression. (a) Diagram of early mouse segmented hindbrain illustrating the partition of the dorsal neuroepithelium along the DV axis. Diagrams of sagittal sections at the cerebellar uRL level (b1, c, d) or coronal sections at the precerebellar lRL level (b2, e). The entire WT RL (a, b) is encompassed by Wnt1 expression. The RL is further partitioned in DV subdomains of progenitors, according to the expression of specific transcription factors. Lmx1a-expressing progenitors (orange) represent the primordium for nonneuronal RL-derived roof plate (RP) and choroid plexus (CP) lineage (b1, b2, orange dashed lines). Math1-expressing progenitors (red) form in the uRL the primordium for cerebellar glutamatergic neurons (b1); in the precerebellar lRL the primordium of mossy fiber (MF) neurons (b2). Math1 derivatives first migrate tangentially along external migratory pathways at the surface of the cerebellum or ventral hindbrain (b1, b2, red dashed lines, and red arrows 1), before entering into it by an outside-in radial migration (b1, red arrow 2). The VZ adjacent to the Math1expressing domain (b1, green; b2, red–green stiped key) is characterized by the expression of Ngn1, Ngn2, Mash1, and/or Ptf1a. In the cerebellar primordium, VZ progenitors mostly produce GABAergic neurons, which migrate radially with an inside–out orientation (b1, green arrows). In the lRL, the dorsal VZ adjacent to the precerebellar Math1þ RL selectively express Olig3, as partly Pax6, Ptf1a, Ngn1, and Mash1 (b2, red–green striped key). This part of the dorsal VZ generates climbing fiber (CF) ION precursors that migrate tangentially into an ‘intramural’ pathway (b2, red–green dashed lines and red arrow 2). The ION progenitor domain seems to lie mostly in the Olig3/Ptf1a overlapping domain, although its exact DV extent is still ill defined. (c) Math1 expression can be abnormally induced in progenitors contacting cerebellar VZ cells that have been respecified by ectopic Lmx1a overexpression. (d) Inhibition of Notch1 signaling results in the expansion of the Math1þ domain at the expenses of the VZ. (e) Pax6 inactivation perturbs the balance between MF and CF RL by triggering a size reduction of the Math1þ-expressing domain associated with an expansion of Ngn1-expressing domain.

21.2.2.1.1 LMX1A EXPRESSION DEFINES NONNEURONAL RL LINEAGES

Expression of the LIM HD TF Lmx1a and the growth differentiation factor 7 (Gdf7) delineates the dorsal-most Wnt1þ subdomain defined as nonneuronal RL, forming the primordia of roof plate and choroid plexus lineages (Figures 21.3 and 21.4; Chizhikov et al., 2006; Currle et al., 2005; Hunter and Dymecki, 2007; Landsberg et al., 2005; Ray and Dymecki, 2009). The expression of Lmx1a is sufficient to engage RL progenitors into a roof plate differentiation pathway, as overexpression generates excessive roof plate cells (Chizhikov et al., 2006). Nevertheless, Lmx1a inactivation

in the dreher mice affects the development of the roof plate only partially, suggesting potential redundancy with other factors (Chizhikov et al., 2006). Late Wnt1þ/ Lmx1aþ RL progenitors that directly contribute to the choroid plexus also express Gli1, a TF-activated downstream of the sonic hedgehog (Shh) signaling pathway (Huang et al., 2009; Hunter and Dymecki, 2007). The choroid plexus acts as a late primary source of Shh and stimulates its own expansion (Huang et al., 2009). Indeed, Shh signaling is needed to regulate the proliferation and maintenance of this late Wnt1þ/ Lmx1aþ/Gli1þ progenitor pool of the lRL (Huang et al., 2009).

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21.2.2.1.2 MATH1þ RL PROGENITORS GIVE RISE TO MULTIPLE SUBPOPULATIONS OF TANGENTIALLY MIGRATING NEURONAL DERIVATIVES

Math1 (Atoh1) encodes a bHLH TF and is the mouse ortholog of the proneural Drosophila gene atonal. Starting at E9.5, Math1 is expressed throughout the entire RL rostrocaudal axis in a domain adjacent to the nonneuronal Lmx1aþ RL (Figure 21.4(a) and 21.4(b); Akazawa et al., 1995). Loss of cerebellar granule neurons was initially described in Math1-deficient mice (Ben-Arie et al., 1997), and later analysis of Math1-deficient chimeras demonstrated its cell-autonomous requirement in granule cell progenitors (Jensen et al., 2004). All the remaining cerebellar neurons were thought to be generated from the Math1 cerebellar ventricular zone (Wang and Zoghbi, 2001). In past years, Math1þ progenitor fate-mapping experiments in the mouse revealed additional uRL lineages (Figure 21.3). Starting at E9.5, the Math1þ uRL generates a rostral migratory stream that contributes to pontomesencephalic neurons such as the parabrachial nuclei, the mesopontine tegmental system, and the lateral lemniscus (Machold and Fishell, 2005; Wang et al., 2005). These nuclei are important components of the proprioceptive/ vestibular and auditory systems, respectively (Balaban et al., 2002; Friauf, 1994). Subsequently, the Math1þ progenitor domain of the uRL gives rise sequentially to distinct cohorts of tangentially migrating populations that include the projection neurons of the deep cerebellar nuclei (starting from E10.0) and the unipolar brush cells (from E12.5), in addition to the cerebellar granule neurons migrating into the external granule layer (EGL, from E13.0) (Englund et al., 2006; Fink et al., 2006; Fu¨nfschilling and Reichardt, 2002; Machold and Fishell, 2005; Machold et al., 2007; Wang et al., 2005; Wingate, 2005). Recent fate mapping of Math1þ progenitors also revealed previously unrecognized genetic subdivisions of the lRL, giving rise to cochlear and precerebellar neurons (Farago et al., 2006; Wang et al., 2005). Indeed, the r2–r5 Math1þ auditory RL generates tangential migrating neurons contributing mainly to the ventral cochlear nuclei and the granule neurons of the dorsal cochlear nuclei. Moreover, the r6–r8 Math1þ domain of the precerebellar RL gives rise to mossy, though not climbing fiber neurons: caudally, to the lateral reticular nucleus (LRN) and external cuneate nucleus (ECN); rostrally, to the pontine gray nucleus (PGN) and reticulotegmental nucleus (RTN), collectively referred to as pontine nuclei (PN) (Figure 21.3; Wang et al., 2005). The Math1þ lRL derivatives are also members of the proprioceptive/vestibular/auditory sensory neuronal network and share common characteristics, including a transitory expression of Math1 and a superficial ‘extramural’ mode of tangential migration. Math1 inactivation compromises the development of almost all lRL-derived neurons (Ben-Arie et al., 1997; Bermingham et al., 2001;

385

Englund et al., 2006; Jensen et al., 2004; Maricich et al., 2009; Wang et al., 2005). 21.2.2.1.3 INDUCTION OF MATH1þ RL BY SIGNALING MOLECULES

Induction of unipolar migratory Math1þ precursors occurs at the interface between neural tube and roof plate lineage (Wingate and Hatten, 1999), suggesting that this process relies on ongoing local interactions between these two domains. Accordingly, defects in the roof plate and choroid plexus formation observed in Dreher mutants or roof-plate-ablated embryos, lead to a reduction of the Math1þ domain associated with a decrease in granule cell and precerebellar progenitor number (Chizhikov et al., 2006; Millen et al., 2004; Millonig et al., 2000). Furthermore, the appearance of excessive Math1þ cells adjacent to an ectopic Lmx1ainduced roof plate indirectly confirms its potential inductive activity (Figure 21.4(c)). In contrast, roof plate signaling may control the normal positioning and proliferation of more distal cerebellar ventricular progenitors without being essential to their specification (Chizhikov et al., 2006). In the spinal cord, BMP signaling from the roof plate has been shown to control specification of numerous classes of adjacent dorsal interneurons nonautonomously (Chizhikov and Millen, 2004; Furuta et al., 1997; Helms and Johnson, 2003; Lee and Jessell, 1999). Several lines of evidences suggest that a similar process controls RL induction and specification (Figure 21.5). Roof plate and choroid plexus cells secrete several members of the BMP family of morphogens, including BMP4, BMP5, BMP6, BMP7, and Gdf7 (Alder et al., 1999; Angley et al., 2003). When added to naı¨ve r1 neural tissue in vitro, BMPs can activate a number of granule neuron markers including Math1 and induce the adoption of granule cell morphology (Alder et al., 1999; Wingate and Hatten, 1999). BMP-treated neural cells formed mature granule neurons after transplantation into the early postnatal cerebellum, suggesting that BMPs initiate the program of granule cell differentiation (Alder et al., 1999). Explant coculture experiments further demonstrated that roof-plate-dependent induction of Math1þ cells and their derivatives is significantly blocked by BMP inhibitors in vitro (Chizhikov et al., 2006). Moreover, BMP-receptor-deficient mice lack Math1 expression within the RL (Helms and Johnson, 1998; Wang et al., 2005). In keeping with these data, BMP receptors 1a and 1b are required for the development of cerebellar granule cells (Qin et al., 2006). The roof plate and choroid plexus are likely not the only source of BMPs that influence RL development. A recent study shows that loss of the forkhead TF Foxc1 in the surrounding mesenchyme leads to non-cell-autonomous

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RP and CP lineage Dorsal uRL early progenitor

BMP 7

BMP 4, 5, 6, 7

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FIGURE 21.5

Molecular mechanisms of neuronal RL induction. Cellular and molecular interactions controlling induction of neuronal RL versus VZ progenitor fate in the cerebellar anlage. The roof plate (RP) and choroid plexus (CP) (orange dashed lines) are important dorsal signaling centers secreting several BMPs. Dorsal RL naı¨ve progenitors receive a strong BMP signal (orange arrows) that is sufficient to induce Math1 expression and neuronal RL identity. Math1 autoregulation helps to maintain its own expression, in parallel to BMP7 signaling. Math1 accumulation will activate the expression of Hes5, a transcriptional repressor that cooperate with Hes1 to downregulate Math1 itself. Math1 also directly activates the expression of the BMP antagonist NBL1 as well as the expression of several members of Notch signaling (green arrows), which contribute to antagonize BMP7 signaling and compromise Math1 maintenance. Consequently, Math1 expression is turned off in migrating neuronal RL derivatives. Nevertheless, Math1 transient expression is sufficient to activate Barhl1 expression that is further maintained through an autoregulatory loop. Low BMP signaling reaching more distal VZ progenitors outside the uRL is antagonized by Notch signaling and insufficient to activate Math1 expression. Some VZ progenitors then activate Ptf1a expression that permanently represses Math1 transcription.

abnormalities of the cerebellar RL with the subsequent loss of Math1 in the vermis, a disorganization of the presumptive EGL and a general cerebellar hypoplasia (Aldinger et al., 2009). This misspecification of RL neuronal lineage and late associated cerebellar defects could be due to a decrease of mesenchyme-secreted signaling, including BMP2, BMP4, and Cxcl12 (Aldinger et al., 2009). In addition to BMPs, Notch signaling can also influence RL induction (Figure 21.5). Gain-of-function and loss-of-function experiments in mouse and zebrafish show that the Notch signaling pathway stimulates choroid plexus development by promoting Lmx1þ cell proliferation, thus contributing to the maintenance of this RL-inductive BMP secreting domain (Bill et al., 2008; Dang et al., 2003; Garcia-Lecea et al., 2008; Hunter and Dymecki, 2007; Ray and Dymecki, 2009). Moreover,

Notch1 activity regulates the responsiveness of early uRL progenitor cells to BMP signaling (Figure 21.4(d); Machold et al., 2007). Furthermore, while the activation of BMP signaling in the cerebellar ventricular zone can ectopically induce Math1 expression, this effect can be blocked by the coactivation of the Notch pathway (Figure 21.5; Kretzschmar et al., 1997; Machold et al., 2007). Notch1 activity may prevent the induction of Math1 in the ventricular zone adjacent to the RL by antagonizing the BMP receptor signaling pathway at the level of Msx2 expression (Machold et al., 2007). 21.2.2.1.4 MOLECULAR MECHANISMS OF MATH1 REGULATION IN RL PROGENITORS

Math1 expression is an obligatory step in the acquisition of specific tangential migratory morphologies and properties associated with departure from the RL

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21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES

(Machold and Fishell, 2005; Wang et al., 2005; see below). The modulation of Math1 activity through interaction with the E-protein cofactor Tcf4 within the RL could contribute to the selective specification of different rhombic lip derivative (RLD) programs of differentiation (Flora et al., 2007). Indeed, disrupting Math1/Tcf4 interaction in vivo selectively disrupts PN development without affecting other precerebellar RL-derived nuclei. Thus, Math1/E-protein heterodimers might interact with distinct cell-specific transcriptional cofactors to activate specific spatiotemporal differentiation programs in RLDs differentially. Positive and negative regulatory loops control the maintenance of Math1 expression (Figure 21.5). On the one hand, Math1 may maintain its own promoter activity though the interaction with a specific E-box binding site (Figure 21.5; Helms et al., 2000). On the other hand, a negative regulatory feedback loop involves Hes5, a transcriptional repressor known to antagonize Math1. Math1 can directly activate Hes5 transcription by binding an E-box-containing enhancer flanking this gene and stimulates Hes5 expression in vivo. Indeed, Hes5 is downregulated in Math1-deficient RL tissue and primary cultures (Gazit et al., 2004). Hes5 accumulation will in turn lead to the downregulation of the transcription of Math1 itself. The expression of another transcriptional repressor of Math1, namely, Hes1, appears to be independent of Math1 in the RL (Figure 21.5; Gazit et al., 2004; Zheng et al., 2000). Moreover, Math1 directly activates the expression of the BMP antagonist NBL1. NBL1 enables differentiation of Math1 null rhombic lip-derived cells in culture by antagonizing the antidifferentiative effect of BMP7 (Figure 21.5; Krizhanovsky and Ben-Arie, 2006). Math1 expression is transient in most of the RL lineage, with the exception of the granule cell progenitors of the cerebellar EGL that maintain Math1 expression during their extended proliferative state. The maintenance of such proliferative state is notably regulated by Notch2 (Solecki et al., 2001) and Shh signaling (Dahmane and Ruiz i Altaba, 1999; Lewis et al., 2004; Wallace, 1999; Wechsler-Reya and Scott, 1999), and it requires the activity of zinc finger TFs such as Zipro1 (formerly RU49, Yang et al., 1996, 1999) and Zic1 (Aruga et al., 1998; Ebert et al., 2003). Zic1, whose expression in the EGL is also induced by BMP signaling, acts as a direct repressor of Math1 expression. Zic1 can interact with a conserved site within the Math1 enhancer and block the autoregulatory activity of Math1 itself (Ebert et al., 2003). Math1 downregulation will only occur in postmitotic granule neuron precursors that exit the cell cycle before progressing in their program of differentiation by migrating radially from the EGL toward the inner granule cell layer (Figure 21.4(b)). Thus, the final inactivation of Math1 will mark an irreversible transition into the migratory program.

387

21.2.2.1.5 PROGENITORS OF THE INFERIOR OLIVARY NEURONS ARE GENERATED VENTRALLY TO THE MATH1þ DOMAIN AND IDENTIFIED BY SPECIFIC TFS

Unlike mossy fiber precerebellar neurons, the RL progenitors of the inferior olivary neurons (ION), a main source of climbing fibers, are excluded from the Math1þ lRL domain and do not require Math1 to migrate and develop properly (Ray and Dymecki, 2009; Wang et al., 2005). Fate-map analysis of lRL demonstrated that the ION progenitor domain arises from the ventral low-expressing portion of the Wnt1þ neuroepithelium (Figures 21.3, 21.4(a), and 21.4(b); Landsberg et al., 2005). This ventral lRL domain is further partitioned in molecularly distinct progenitor pools (Figure 21.4(a) and 21.4(b)). Moving from dorsal to ventral, the domain is defined by the expression of the TF Ngn1, Mash1, and Ptf1a, the latter overlapping with Mash1 in the ventral Wnt1þ RL domain (Hoshino et al., 2005; Landsberg et al., 2005; Liu et al., 2008). Indeed, the Ptf1aþ progenitor pool generates most of the ION, except those of the posteroventral and posterodorsal ION subnuclei that may be contributed by Ngn1þ and/or Mash1þ pools (Landsberg et al., 2005; Ray and Dymecki, 2009). The inferior olivary complex is largely composed of glutamatergic excitatory neurons, but it also contains a small number of GABAergic inhibitory neurons (Fredette et al., 1992). Ptf1a::Cre lineage tracing experiments showed that Brn3aþ glutamatergic ION are derived from the Ptf1aþ progenitor cells of the lRL and that a Ptf1a null mutation results in a dramatic loss of ION (Hoshino et al., 2005; Yamada et al., 2007). In these mice, the generation of Brn3aþ neurons was not compromised, but these neurons failed to migrate into the ION area, subsequently undergoing apoptosis (Yamada et al., 2007). Thus, Ptf1a function may be dispensable for glutamatergic fate determination though necessary for ION migration and/or differentiation. Furthermore, in Ptf1a-deficient mice, progenitor cells may switch and produce mossy fiber instead of climbing fiber neurons, suggesting that Ptf1a expression may prevent activation of Math1 in RL progenitors (Figure 21.5; Yamada et al., 2007). In a manner similar to mossy fiber neurons, the climbing fiber neurons of the inferior olive complex migrate tangentially as well. However, in contrast to the ‘extramural’ pathway followed by mossy fiber neurons, climbing fiber neurons migrate ‘intramurally’ in the hindbrain parenchyma (Figure 21.4(b); Ray and Dymecki, 2009; Sotelo, 2004). The fact that both ION and mossy fiber neurons migrate tangentially, though with distinct routes, suggests that their progenitors could share some common properties. Recent fate-map and functional studies (Liu et al., 2008; Storm et al., 2009) revealed that the expression domain of the TF

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21. TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION IN THE VERTEBRATE HINDBRAIN

Olig3 in the caudal hindbrain spans the entire lRL, including both the ION and mossy fiber neuron progenitor domains, thus currently providing the most reliable molecular marker for precerebellar RL (Figure 21.4(b); Ray and Dymecki, 2009). In Olig3-deficient mice, Math1 expression is partially downregulated, resulting in a reduction of the four mossy fiber nuclei in the brainstem (Liu et al., 2008; Storm et al., 2009). Moreover, the ION is almost completely lost (Liu et al., 2008; Storm et al., 2009). In addition, gain-of-function experiments by electroporation in the chick neural tube indicated that Olig3 can cooperate with Ptf1a to determine the expression of Foxd3 and the fate of ION (Storm et al., 2009). Finally, the Pax6 TF is expressed in a region of the precerebellar lRL overlapping the Math1þ and Ngn1þ domains (Figure 21.4(b); Landsberg et al., 2005). Pax6 inactivation results in expansion of the lRL Ngn1þ domain at the expense of the Math1þ territory (Figure 21.4(e)). As predicted by the genetic fate maps, this abnormal lRL patterning leads to an enlargement of the climbing fiber nucleus and reductions in all four major mossy fiber nuclei (Engelkamp et al., 1999; Landsberg et al., 2005). Thus, Pax6 may indirectly regulate Math1þ expression in RL progenitors through potentiation of BMP signaling. Indeed, the lack of Pax6 significantly reduces Msx1, Msx2, and Msx3 expression, which are transcriptional target genes of BMP signaling (Engelkamp et al., 1999). 21.2.2.2 Transcriptional Control of General Properties of RLD Tangential Migration The molecular pathways involved in stereotypical tangential migration of RLDs, including granule cells precursors and precerebellar neurons, have recently begun to be characterized. RLDs have a unipolar morphology with a single leading process sensing the environment and a nucleus moving within this process through nucleokinesis (Kawauchi et al., 2006; Marin et al., 2006). The growth of the leading process and nucleokinesis depends on the rearrangements of the cytoskeleton in response to chemotropic factors that directly influence the progression of migrating neurons (Bloch-Gallego et al., 2005; Marin et al., 2006; Marcos et al., 2009b; and references therein). RLDs undergo a superficial neurophilic migration by forming chains in close contact with each other or by adhering at the surface of preexisting dorsoventrally projecting commissural axons. The expression of adhesive molecules such as TAG1 and cadherins confers to RLDs special homotypic and heterotypic adhesive properties essential for their migration (Backer et al., 2002; Kyriakopoulou et al., 2002; Rieger et al., 2009; Taniguchi et al., 2006; Wolfer et al., 1994; Yee et al., 1999). Cadherin-2 links adhesive properties to cytoskeletal and centrosome

rearrangements that support cell polarization during migration (Rieger et al., 2009). As discussed above, Math1 and Pax6 contribute to RLD specification in response to roof plate cell signaling. Their inactivation impairs the initial differentiation of newly induced RL progenitors into tangentially migrating neurons. For instance, in the small eye (sey)/Pax6mutant mice, PN precursors fail to extend a normal leading process and to enter their anterior extramural migratory pathway (Engelkamp et al., 1999). Thus, the reduction of the four mossy fiber nuclei observed in Pax6 mutants could be due to both specification and migration defects. Math1 expression is normally downregulated in all migrating RLDs, with the exception of granule cells precursors. Nevertheless, Math1 contribution to the control of RLD tangential migration could be indirectly achieved via the activation of factors that are directly required for tangential migration. The HD TF of the BarH class, Barhl1 and Barhl2, are two downstream targets of Math1 (Figure 21.5, Bermingham et al., 2001; Saba et al., 2005). Barhl1 is expressed through the entire AP extent of the RL, as well as throughout RLD migration (Li et al., 2004). Analysis of Barhl1deficient mice indicates that this TF is dispensable for initial fate determination, but required for the correct migration and survival of both precerebellar and cerebellar granule neurons (Li et al., 2004). All mossy fiber precerebellar neurons are consequently reduced in size (Li et al., 2004). Barlh1 requirement for RLD survival could be mediated through regulation of NT-3 neurotrophin signaling (Li et al., 2004). Moreover, an enhancer element 50 to the Barhl1 gene that is needed to drive high-level and cell-specific expression in RLD neurons has been recently identified (Chellappa et al., 2008). Such enhancer contains two binding sites for both Barhl1 and Barhl2, thus allowing for auto- and crossregulation of Barhl1 own expression and maintenance, whereas Math1 may be required for proper initiation of Barhl1 expression (Figure 21.5; Chellappa et al., 2008). Other TFs contribute to RLD migration. For instance, genes of the nuclear factor I (NFI) family, including NFIA, NFIB, NFIC, and NFIX, are coexpressed in the RL and their derivatives (Chaudhry et al., 1997; Kumbasar et al., 2009; Mason et al., 2009; Wang et al., 2004, 2007). Inactivation experiments have shown that NFIA and NFIB cooperate as key regulators of postmitotic granule cell neuron development, including axon formation, dendritogenesis, and migratory behavior (Wang et al., 2007). EphrinB1, N-cadherin, and Tag1 were identified as direct NFI target genes mediating these effects (Wang et al., 2007, 2010). Concerning precerebellar neuron development, NFIA and NFIX null mice do not display obvious abnormalities (Kumbasar et al., 2009). On the contrary, NFIB inactivation leads to a decrease in PN progenitor neurogenesis associated with

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21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES

a developmental delay in the migration of all mossy fiber neurons and a reduction of the prospective nuclei (Kumbasar et al., 2009; Steele-Perkins et al., 2005). Similar to granule cell neurons, NFIB function in precerebellar neurons could be partly mediated through activation of N-cadherin and Tag1 expression. Indeed, N-cadherin knockdown mimics a developmental delay by slowing the migration of LRN and ECN neurons (Taniguchi et al., 2006). In addition, perturbation of Tag1-mediated neuronal interactions results in an alteration of the LRN/ECN migratory behavior in vitro (Kyriakopoulou et al., 2002) that is associated with an increased cell death in vivo (Denaxa et al., 2005). 21.2.2.3 Distinct Responses to Midline Signaling and Directionality of Migration The TFs and other molecules described above are part of a generic program of differentiation and tangential migration associated with the RLD fate. Nearly all such molecular markers are expressed uniformly throughout the AP axis in the RL and/or RLD neurons. Nevertheless, in spite of this apparent homogeneity, there is a manifest RLD heterogeneity along the AP axis. This is evident in the choice of RL precursors of distinct migratory pathways and in the variable responsiveness (i.e., local attraction or repulsion) of distinct rostrocaudal populations of RLD to floor plate signaling (Figures 21.6(a) and 21.7(a); see below). Indeed, while the entire AP extent of the hindbrain floor plate is an important source of diffusible guiding factors, including Netrin1, Slit1, Slit2, and Slit3 (Bloch-Gallego et al., 1999; Di Meglio et al., 2008; Geisen et al., 2008; Gilthorpe et al., 2002; Marillat et al., 2004), each rostrocaudal RLD population (e.g., granule neuron, cochlear, or precerebellar precursors) express a selective repertoire of membrane receptors for Slit, namely, Robo1-3 receptors, and for Netrin, namely, the DCC or Unc5H receptors mediating attraction or repulsion, respectively (Figures 21.6(a) and 21.7(a); Howell et al., 2007; see below). Therefore, RLDs represent a suitable model by which to investigate how transcriptional regulation can influence the local guidance of tangentially migrating neurons through the dynamic regulation of the expression of receptors for key guidance molecules. 21.2.2.4 Transcriptional Control of the Directionality of uRL-Derived Granule Cell Migration The tangential migratory pathway used by granule cell precursors to form the EGL is restricted to the surface of dorsal cerebellum and does not progress through its lateral edge in direction of the ventral midline (Figure 21.6(a)). This behavior, distinct from posterior precerebellar RLDs (see below), could be partly due to distinct sensitivity to the floor-plate-derived Netrin1

389

signaling. Granule cells emerging from the uRL do not show significant response to Netrin1, while granule cells cultured from EGL explants are strongly repelled by this factor (Alcantara et al., 2000). Indeed, EGL cells express several Netrin receptors, including DCC, and repulsive receptors of the Unc5h family, including Unc5h2 and Unc5h3 (Ackerman et al., 1997; Alcantara et al., 2000; Hong et al., 1999; Leonardo et al., 1997; Przyborski et al., 1998). Thus, Netrin1 may act as a chemorepulsive signal on EGL cells through interaction with Unc5h receptors (Figure 21.6(a)). Accordingly, Unc5h3 inactivation affects cerebellar development by allowing granule cells and Purkinje cells precursors to colonize ventrally adjacent pons and midbrain regions ectopically, thus corresponding to a displacement toward the midline floor plate because of a loss of chemorepulsive response to Netrin1 by migrating granule cells (Ackerman et al., 1997; Goldowitz et al., 2000; Przyborski et al., 1998; but see below). Although Unc5h receptors can bind Netrin1 directly, the repulsive response was suggested to be mediated through the formation of a complex between Unc5h and DCC receptors (Hong et al., 1999). Therefore, in this system, Unc5h3 may be cell-autonomously required to restrain granule cell migration into the cerebellar presumptive territory, and in turn such cells restrict Purkinje cell spatial distribution (Ackerman et al., 1997; Goldowitz et al., 2000; Przyborski et al., 1998). However, such a model is challenged by the fact that cerebellar development is unperturbed in the Netrin1 knockout mouse (Bloch-Gallego et al., 1999). This raises obvious questions about the existence of compensatory mechanisms contributing to the restriction of granule cell migration to the cerebellum. Among such potential mechanisms, it is noteworthy that Slit repels migrating granule cell precursors through direct interaction with Robo2 in vitro (Gilthorpe et al., 2002; Guan et al., 2007), thus suggesting that Slit signaling represses ventral migration of cerebellar EGL cells in parallel to Netrin1-mediated signaling. Such a hypothesis could be tested by inactivating both pathways in vivo. On the transcriptional level, the distinctive expression of Unc5h3 in EGL cells is dependent on Pax6 function (Figure 21.6(a)). Indeed, in the small eye (sey) mutant, the loss of Pax6 causes a lack of Unc5h3 expression in the EGL that correlates with ectopic migration of granule cells out of the cerebellum (Engelkamp et al., 1999). On the other hand, the normal lack of ventral tangential migration of granule cell precursors toward the floor plate may also be related to the specific AP origin and Hox expression status of EGL progenitors. Granule cell progenitors are generated from the r1 RL, and they do not express any Hox gene, unlike progenitors of the lRL (Figure 21.2; see below). Targeted overexpression of Hoxa2 in avian r1 RL leads to cell-autonomous respecification of the directionality of their tangential migratory

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21. TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION IN THE VERTEBRATE HINDBRAIN

Cerebellum Midbrain EGL uRL (r1)

1 2 3

Precerebellar IRL (r6–r8)

PN (AES)

Floor plate Slit1, 2, 3 r4 Netrin1

Floor plate Slit1, 2, 3 Netrin1

Spinal cord

PN

WT 1

2

3

Repulsion

Repulsion

Attraction

Pax6

Nscl1-2

DCC

UNC5h3 DCC Robo2

Robo3 inactive

(a) Netrin1 (fp)

Slit1,2,3 (fp)

Netrin1 (fp)

Hoxa2

Nscl1-2

Robo1 Robo2

DCC

Slit1,2,3 (fp)

Wnt1::Cre; Hoxa2 cKO Attraction Nscl1-2

Hoxa2

Robo3 Robo1 active Robo2

Netrin1 (fp)

DCC

Robo1 Robo3 Robo2 active

Slit1,2,3 (fp)

(b)

Netrin1 (fp)

Slit1,2,3 (fp)

PN

Floor plate Slit1, 2, 3 Netrin1

Floor plate Slit1, 2, 3 Netrin1

PN Spinal cord

DCC KO Robo1/Robo2 KO Attraction Nscl1-2

DCC

(c)

Hoxa2

Robo3

Netrin1 (fp)

Slit1,2,3 (fp)

Robo3 KO Repulsion Nscl1-2

DCC

(d) Netrin1 (fp)

No

Attraction

Hoxa2

Hoxa2

Robo1 Robo2

Robo3 Robo1 active Robo2

Slit1,2,3 (fp)

Slit1,2,3 (fp)

Nscl1/Nscl2 KO Repulsion Pax6

UNC5h3 DCC

Netrin1 (fp)

Hoxa2

Robo3 Robo1 active Robo2

Slit1,2,3 (fp)

FIGURE 21.6 Transcriptional regulation of directional tangential migration of PN. (a–d) Diagrams of E15.0 mouse hindbrain (lateral view). (a) In WT mice, progenitors emerging from the uRL and migrating into the external granule cell layer (EGL) are repelled by Slit and Netrin1 secreted at the level of the floor plate (FP), which contribute to restrain their migration ventrally (1). Pax6 is a positive regulator of the Unc5H3 receptor that mediates Netrin1 repulsion. PN originate in the r6–r8 precerebellar lRL and follow a tangential migratory pathway in two successive phases. After migrating out of the RL, PN first migrate rostrally in the anterior extramural stream (AES) through several rhombomere-derived territories (2). After reaching r3, PN turn ventrally and migrate to settle within the r4-derived domain (3). Attractive Netrin1 and repulsive Slit1-3 are secreted at the level of the FP, whereas Hoxa2, DCC, Robo1-3, and Nscl1-2 are expressed in migrating PN. (b) Hoxa2 is required to maintain sustained Robo2 expression within migrating PN, as assessed in Wnt1::Cre; Hoxa2flox/flox conditional KO fetuses. Lack of Hoxa2 results in neurons prematurely migrating ventrally at ectopic posterior locations. (c) Compound Robo1/Robo2 KO phenocopies the lack of Hoxa2 showing PN prematurely attracted toward the ventral midline. In both (b) and (c), diminished Slit/Robo repulsive signaling during rostral migration becomes insufficient to overcome Netrin1/DCC attraction. (d) PN migratory defects in DCC, Robo3, and Nscl1/Nscl2 KOs. In all cases, PN properly follow the first phase of rostral migration but are unable to turn ventrally and approach the r4 FP. PN lacking DCC are insensitive to Netrin1 attraction, which is essential only during the second phase of ventral migration. Similarly, lack of Robo3 prevents silencing of Robo1/Robo2-mediated repulsion, thus making PN unable to switch from repulsion to attraction and to progress toward the FP in r4. Finally, Nscl1/Nscl2 appears necessary both as positive regulators of DCC and to repress Unc5h3 receptor expression in migrating PN. In Nscl1/Nscl2 KO, netrin1 repels PN prematurely.

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21.2 BREAKING BOUNDARIES: TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION ACROSS RHOMBOMERES

391

FIGURE 21.7 PN tangential migration and FMN sigMidbrain

Cerebellum

Midbrain

Cerebellum

Precerebellar RL (r6–r8) LRN/ECN (PES) Spinal r5–6 cord

Floor plate Slit1, 2, 3 Netrin1

Precerebellar RL (r6–r8)

PN (AES) Floor plate Slit1, 2, 3 Netrin1

r4

Spinal cord

Facial Slit2, 3

PN:

LRN/ECN:

Repulsion

Attraction Hoxa2

Nscl1-2

Robo3 Robo1 Robo2 active

DCC

(a)

Netrin1 (fp)

Floor plate Slit1, 2, 3 Netrin1

Nscl1-2

Slit1,2,3 (fp)

Floor plate Slit1, 2, 3 Netrin1

PN

Robo3 Robo1 Robo2 inactive

DCC

(b)

Hoxa2

+

Netrin1 (fp)

r4

PN

Facial Slit2, 3

Facial Slit2, 3

Hoxa2 KO

Wnt1::Cre; Hoxa2 cKO

Attraction

Attraction

Nscl1-2

Nscl1-2

Robo3 Robo1 Robo2

DCC

(c)

Floor plate Slit3 Netrin1

Slit2,3 (FMN) Slit1,2,3 (fp)

Netrin1 (fp)

Slit1,2,3 (fp)

Robo3 Robo1 Robo2

DCC

(d)

Netrin1 (fp)

+

Slit2,3 (FMN) Slit2,3 (fp)

PN

PN Facial Slit3

Slit1/Slit2 KO

Phox2b KO

Attraction

Attraction

Nscl1-2

DCC

(e)

Hoxa2

Nscl1-2

Robo3 Robo1 Robo2

Netrin1 (fp)

+

Slit3 (FMN) Slit3 (fp)

DCC

(f)

Hoxa2

Robo3

Netrin1 (fp)

Robo1 Robo2

Slit1,2,3 (fp)

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naling. Diagrams depicting lateral views of E12.0 (a) and E15.0 (b–f) mouse hindbrain. (a) LRN/ECN progenitors emerging from the precerebellar RL between E12.0 and E14.0 are strongly attracted by Netrin1 and migrate ventrally directly to the floor plate in the posterior extramural stream (PES) (green arrows). During the same period, FBM neurons migrating from r4 begin to reach their final position in r6 (gray shadowing and red dashed lines). (b) FBM neurons secrete Slit2 and Slit3. Progressive ventral accumulation could increase Slit repulsive signaling emanating from the FMN and faced by newly generated precerebellar RL derivatives; this could inhibit their further ventral migration into the posterior hindbrain. After E14, migrating RLDs may be thus forced to follow the anterior migratory pathway and to adopt PN fate. (c) PN migratory defects observed in Hoxa2 full KO are due to both downregulation of Robo2 in PN and the decrease of Slit expression into the FMN. (d) Conditional Hoxa2 inactivation in PN that does not affect FMN expression of Slit causes milder though sizeable PN migration defects. (e) In Slit1/Slit2 double KO, Slit/Robo signaling is not sufficient to prevent premature ventral PN migration, despite the presence of FMN and persistent expression of Slit3. (f) A similar phenotype is observed in Phox2b KO that totally lack FMN. Thus, Slit secretion from the floor plate is not sufficient to repel and drive all PN migrating anteriorly.

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21. TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION IN THE VERTEBRATE HINDBRAIN

program (Eddison et al., 2004). Instead of migrating dorsorostrally and contributing to the EGL, Hoxa2þ transfected r1 derivatives violate the cerebellar territory to migrate ventrally toward the midline (Eddison et al., 2004), suggesting a dramatic change from repulsion to attraction of their normal sensitivity to Netrin1. Such a behavior can be interpreted as a posteriorization of their positional identity, since ectopic r1 RL derivatives acquire a migratory pathway and a final position reminiscent of more posterior lRL derivatives (Eddison et al., 2004). In conclusion, the early acquisition of a Pax6þ/Hoxa2 transcriptional code enables EGL progenitors with a specific positional address intersecting along the AP and DV axes, which may intrinsically determine their repulsive response to Netrin1 and migratory directionality (Figure 21.6(a)). 21.2.2.5 Transcriptional Control of Directionality of Mossy Fiber LRL-Derived Precerebellar Neuron Migration In contrast to EGL cells, all migrating neurons issued from the posterior precerebellar RL, including ION and all mossy fiber neurons, are attracted by Netrin1 in vitro through its interaction with DCC (Alcantara et al., 2000; Causeret et al., 2002; de Diego et al., 2002; Stein and Tessier-Lavigne, 2001; Taniguchi et al., 2002; Yee et al., 1999). r6- to r8-derived mossy fiber neurons form two distinct migratory groups according to their birthdates and initial migratory directions, the so-called anterior extramural stream (AES) and posterior extramural stream (PES) (Figures 21.6(a) and 21.7(a); Altman and Bayer, 1987b,c). LRN/ECN postmitotic precursors are generated earlier and are directly under the influence of Netrin1-mediated attraction: they migrate tangentially with a DV direction toward the midline (Figure 21.7(a); Marcos et al., 2009a). LRN/ECN neurons normally cross the floor plate and switch their response to the midline from attraction to repulsion through the activation of Robo1 and Robo2 receptors (Di Meglio et al., 2008; Taniguchi et al., 2002). This change is directly linked to the downregulation of Robo3/Rig1 receptor expression after midline crossing. Indeed, Robo3 acts in precerebellar neurons, as in other commissural systems, as a negative regulator of Slit responsiveness by silencing Robo1/ Robo2-mediated activity (Di Meglio et al., 2008; Marillat et al., 2004; Sabatier et al., 2004). In turn, Robo1/Robo2 can mediate the response to Slit repulsive activity and the silencing of Netrin1/DCC-mediated attraction at the midline (Causeret et al., 2002; Stein and Tessier-Lavigne, 2001), allowing LRN and ECN neurons to migrate contralaterally and reach their lateral and dorsal final positions, respectively (Di Meglio et al., 2008). In contrast, PN emerge later from the same r6–r8 domain of the precerebellar RL and choose a distinct migratory pathway. After a short DV migration, PN

precursors migrating into the AES progress caudorostrally through several rhombomere territories from r6– r8 to r4, before turning again ventrally and reaching a final position on both sides of the floor plate in r4 (Figure 21.6(a); Geisen et al., 2008). Therefore, PN precursors are peculiar in that; unlike LRN/ECN precursors, they are unable to progress all the way down toward the medullary midline but turn rostrally shortly after exiting from the precerebellar RL. Recent work shows that the choice of ventral versus rostral migration is dependent on the neuronal response to midline signaling and functional interaction between Slit and Netrin1 pathways (Figure 21.6(a); Geisen et al., 2008; Marcos et al., 2009a; Yee et al., 1999; see below). Additional signals must be involved in attracting PN anteriorly and/or repulsing them from the posterior hindbrain. Chemoattraction of PN could be provided by the meninges that overlay the migrating AES. The meninges secrete the chemokine CXCL12 (SDF1) and enhance the tangential migration of CXCR4-expressing cortical hem-derived Cajal-Retzius cells (Borrell and Marin, 2006; Zhu et al., 2009). Migrating PN also express CXCR4, and the AES anterior migration is disrupted in SDF1- and CXCR4-deficient animals (Vilz et al., 2005; Zhu et al., 2009). Interestingly, CXCL12 (SDF1)/ CXCR4 signaling can be modulated by Slit on Robo binding to CXCR4 and provide directional migration (Wu et al., 2001), suggesting an integration of AP and DV directional migratory mechanisms. The following section provides insights into how such stereotypical directional responses of tangentially migrating neurons to multiple and simultaneous guidance cues may be regulated at the transcriptional level. 21.2.2.5.1 HOX TFs CONTROL DIRECTIONAL MIGRATION OF PN

The Hox class of TFs is important regulators of the directionality of PN migration along the AP axis (Geisen et al., 2008). Notably, postmitotic PN express paralog group (PG)2–5 Hox genes throughout their migration and settling in pontine nuclei, thus maintaining a Hox code appropriate for their axial level of origin from the r6–r8 RL (Geisen et al., 2008). In both Hoxa2and Hoxb2-mutant mice, although with different penetrance and severity, subsets of PN prematurely turn ventrally toward the midline during their rostral phase of migration and eventually settle in small ectopic ventral nuclear formations posterior to the normal location of pontine nuclei (Figures 21.6(b), 21.7(c), and 21.7(d)). Such ectopically migrating neurons are prematurely attracted to the midline while maintaining normal expression of DV guidance molecules such as Rig1/Robo3 and DCC, as well as Pax6, Barlh1, and TAG1, suggesting that their PN identity is not affected (Geisen et al., 2008). In addition, comparison of null and conditional mutant

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21.3 CONCLUSIONS AND PERSPECTIVES

mice indicated that Hox PG2 genes are required in both a cell-autonomous and a non-cell-autonomous manner in order to maintain the normal rostral migratory route of the AES and prevent PN premature ventral migration (Figures 21.6(b), 21.7(c), and 21.7(d)). One possibility is that Hox PG2 genes regulate the response of PN to repulsive environmental cues antagonizing the DV attraction system, thus allowing the progression along the rostral migratory route. Indeed, compound Robo1/ Robo2-, Slit1/Slit2-, and Robo2/Slit2-mutant mice displayed PN migratory defects that phenocopied those observed in Hox PG2 mutants (Figure 21.6(c); Geisen et al., 2008). The receptor Robo2, expressed in pontine migrating neurons, is a direct target of Hoxa2 (Geisen et al., 2008). Thus, Hoxa2 may be required to maintain normal Robo2 expression levels, preventing precocious ventral migration of PN and allowing their progression along the rostral migratory route (Figure 21.6(b)). In the absence of Netrin1, DCC, or Robo3 (BlochGallego et al., 1999; Marcos et al., 2009a; Marillat et al., 2004; Yee et al., 1999), PN manage to leave the RL and turn rostrally, but they are unable to undertake the final step of ventrally oriented migration toward the floor plate of r4. PN stop at ectopic dorsal position, where they form aggregates resulting in lack of the PGN (Figure 21.6(d)); Marillat et al., 2004; Yee et al., 1999). Thus, attraction to the midline may require both attraction mediated by the Netrin1/DCC system and silencing by Robo3/Rig1 of Robo1/Robo2-mediated repulsion in response to Slit midline signaling (Figures 21.6(d)). The Nscl1 and Nscl2 bHLH TFs may control the transition between rostral and ventral phases of migration and progression of PN into ventral r4. Indeed, the corresponding mutants were shown to phenocopy Netrin1, DCC or Robo3 phenotype by affecting the final phase of ventral migration (Figure 21.6(d); Schmid et al., 2007). Such defect correlates with a cell-autonomous downregulation of DCC that could cause a general decrease in Netrin1 responsiveness, such that PN might not be able to overcome the Slit-mediated repulsion. Furthermore, in the Nscl1/ Nscl2 double knockout, Unc5h3 is prematurely activated during PN migration (Schmid et al., 2007), instead of just at the midline (Alcantara et al., 2000; Bloch-Gallego et al., 1999). Unc5h3 premature activation could additionally contribute to a repulsive response to Netrin1 activity and interfere with the ability of PN to approach the ventral midline when reaching r4 (Figure 21.6(d)). Despite many studies on precerebellar RLD development, it is still not clear which signal(s) make ECN and LRN neurons choose to migrate along the PES, whereas PN choose the AES. Recently, it was shown that the facial motor nucleus (FMN) is an important signaling source of secreted Slits, namely, the FMN strongly express Slit2 and Slit3 (Figure 21.7(b); Geisen et al., 2008). Moreover, there is a temporal correlation between the completion

393

of the posterior migration of the Slit-secreting FBM neurons and the onset of the rostral migration of the AES (Figure 21.7(a) and 21.7(b)). The bulk of FBM neurons tangentially migrating from r4 reach their final location in ventral r6 around E13.5. Thus, the progressive temporal accumulation of FBM neurons may increase the amount of Slits secreted into the dorsal hindbrain, which, in turn, could help prevent further ventral migration of r6–r8 mossy fiber neurons toward the ventral midline and force the later born migrating lRL derivatives, for example, the PN, to choose the anterior path (Figure 21.7(b)). Indeed, such an hypothesis was recently corroborated by the analysis of compound Slit mutants and comparison with the phenotype obtained by genetic ablation of the FMN through inactivation of Phox2b, which revealed ectopic ventral migration of PN in both mutant genetic backgrounds (Figure 21.7(e) and 21.7(f); Geisen et al., 2008). In this respect, Slit2 and Slit3 expression are decreased in the FMN of Hoxa2-mutant mice, helping to reduce the overall amount of Slit molecules faced by PN during their anterior migration (Figure 21.7(c); Geisen et al., 2008). Thus, in addition to being intrinsically required in migrating RLDs, Hox PG2 function also contributes extrinsically, i.e. in the migratory environment, to the regulation of the spatiotemporal distribution and/or the levels of guiding cues in the migratory environment. Both functions influence the selection and maintenance by RLDs of the caudorostral migratory path over the dorsoventral one. The migratory behavior of the FBM neurons and final location of FMN vary in different vertebrate species because of specific signaling cues in r5 and r6 (Studer, 2001). Interestingly, rhombomere contributions and migratory pathways of pontine nuclei also vary among vertebrates (Marin and Puelles, 1995). Thus, one possibility is that the distinct migratory behavior of the FMN in different vertebrates may in turn help explain distinct species-specific migratory routes of PN. These results highlight the late roles for the Hox TFs in the control of tangential migration and provide insights into how PN exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into directional neuronal migratory responses.

21.3 CONCLUSIONS AND PERSPECTIVES In this review, the authors have focused on the transcriptional regulation of tangential migration of two well-defined neuronal populations in the developing hindbrain, namely, the FBM neurons, and RLDs. The contribution of transcriptional regulation to tangential migration in other parts of the brain, such as the telencephalon, is outside the scope of the present review.

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21. TRANSCRIPTIONAL REGULATION OF TANGENTIAL NEURONAL MIGRATION IN THE VERTEBRATE HINDBRAIN

However, even though different sets of HD TFs may be at work (indeed, Hox genes, for instance, are expressed only up the rostral hindbrain, not in more anterior parts of the brain), similar sets of signaling and guidance molecules as in the hindbrain are transcriptionally regulated in order to select the specific directionality of tangential WT

migration of interneurons from the ventral telencephalic ganglionic eminences to the cortex, striatum, olfactory bulb, or hippocampus (see Figure 21.8 and Table 21.1 for references; Che´dotal and Rijli, 2009; NobregaPereira and Marin, 2009 for reviews and references therein).

Cortical VZ

WNT signaling +FGF

Dorsal

Gsh2

MGE

Sema 3A/3E

+

St

-

+

Emx1; Emx2

-

Cortical pyramidal neurons MGE Tangential migration Cortical interneurons

Nkx2.1

-

LGE

Ngn1; Ngn2

Cortex

+

Mash1; Dlx1; Dlx2

Pax6

Ventral

Radial migration

+

+

LGE

+ +FGF

(a)

Retinoic-dependent Shh signaling

Ngn2 KO

Nkx2.1 KO

Tangential migration Cortical interneurons Nkx2.1+ /Nrp2-

Lhx6Cre::Nkx2.1 cKO

Striatal interneurons Nkx2.1- /Nrp2+

Nkx2.1 overexpression

Dorsal

Ventral

Cortex

Cortex

LGE

LGE

MGE

Cortex

Cortex

LGE St

MGE

LGE MGE

Sema 3A/3E

St

St

Nkx2.1+ /Nrp2Nkx2.1- /Nrp2+

(b)

FIGURE 21.8 Transcriptional control of neuronal specification and tangential migration in the telencephalon. (a) The diagrams illustrate the partitioning of the telencephalic neuroepithelium in several progenitor domains along the dorsoventral axis, identified by specific transcriptional codes induced by regionalized morphogens activities. Pax6, Emx1/Emx2, and Ngn1/Ngn2 are coexpressed in the progenitors of the dorsal cortical VZ (green) generating radially migrating glutamatergic cortical projection neurons (a, green arrows; Marin and Rubenstein, 2003; Rakic, 2007). Dorsal Wnt signaling contributes to the specification of cells of dorsal telencephalic character through activation of the expression of dorsal markers such as Emx1, Emx2, and Ngn2, while repressing the dorsal extension of the ventral markers Gsh2, Mash1, Dlx2, and Nkx2.1 (Backman et al., 2005; Grove et al., 1998; Gunhaga et al., 2003; Theil et al., 2002). FGF8 may be required for WNT activity that induces induce Emx1 expression (Gunhaga et al., 2003). High Pax6 expression in the dorsal telencephalic VZ directly activates Ngn2 (Scardigli et al., 2003). In cooperation with Ngn1, Ngn2 represses ventral identity by preventing Mash1 expression (Fode et al., 2000) and elicits the generation and differentiation of glutamatergic cortical neurons (Schuurmans et al., 2004). Emx1 and Emx2 act in an additional and partially redundant genetic pathway for the specification of cortical progenitors (Mallamaci et al., 2000; Muzio and Mallamaci, 2003). Gsh2, Mash1, and Dlx1/Dlx2 expressions are restricted to ventral subdivisions of the ventral telencephalon, namely, the lateral ganglionic eminence (LGE), the medial ganglionic eminence (MGE), and the caudal ganglionic eminence (CGE; not shown), while Nkx2.1 expression is restricted to MGE. These TFs are involved in the specification and differentiation of a variety of tangentially migrating GABAergic interneurons, including striatal (essentially from the MGE) (red dashed arrow) and cortical interneurons. Different cortical interneuron subtypes derive from MGE and LGE (red and orange arrows) or from the CGE (not shown) (Anderson et al., 1997, 2001; Che´dotal and Rijli, 2009; Corbin et al., 2001; Flames et al., 2007; Marin and Rubenstein, 2003; Marin et al., 2000; Nobrega-Pereira and Marin, 2009). Retinoids maintain the correct position of dorsal boundaries in the forebrain by both stimulating SHH signaling ventrally and restricting WNT signaling dorsally (Halilagic et al., 2007). Shh controls dorsoventral patterning through activation of Gsh2 (Long et al., 2009; Petryniak et al., 2007). Gsh2 is necessary for Mash1 and Dlx1/Dlx2 expression, which cooperate to repress dorsal regulators including Pax6, Ngn1, and Ngn2 (Toresson et al., 2000) and to direct the program of GABAergic differentiation and migration (Long et al., 2009; Petryniak et al., 2007). The initial MGE patterning requires BMP (Anderson et al., 2002; Spoelgen et al., 2005), FGF (Gutin et al., 2006; Shimamura and Rubenstein, 1997; Storm et al., 2006) and SHH signaling to induce and maintain Nkx2.1-regionalized expression (Chiang et al., 1996; Fuccillo et al., 2006; Goodrich et al., 1997; Storm et al., 2006; Xu et al., 2005, 2010; Yu et al., 2009). SHH signaling in the MGE prevents Gsh2 upregulation and conversion of some MGE progenitors to a CGE- or LGE-like identity (Xu et al., 2010). (b) In the absence of Ngn2, following

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21.3 CONCLUSIONS AND PERSPECTIVES

TABLE 21.1 Bibliographical References Illustrating the Implication of Several TFs in the Control of Either Radial and/or Tangential Migration in the Telencephalon Transcription factor Nkx2.1

Dlx1/Dlx2

Lhx6

COUP-TFII

Radial migration

Tangential migration

Transcriptional target

References

No´brega-Pereira et al. (2008)

Lhx6 (þ)

Transcription factor

Du et al. (2008)

Nrp1, Nrp2 ()

Guiding signaling

No´brega-Pereira et al. (2008)

Arx (þ)

Transcription factor

Cobos et al. (2007) and Colasante et al. (2008)

Nrp2 ()

Guiding signaling

Le et al. (2007)

ErbB4 ()

Guiding signaling

Cobos et al. (2007)

Robo1 ()

Guiding signaling

Cobos et al. (2007)

DSCAM ()

Guiding signaling

Cobos et al. (2007)

Sema3A (þ)

Guiding signaling

Cobos et al. (2007)

MAP2 ()

Cytoskeletal regulator

Cobos et al. (2007)

GAP43 ()

Cytoskeletal regulator

Cobos et al. (2007)

PAK3 (þ)

Cytoskeletal regulator

Cobos et al. (2007)

Arx (þ)

Transcription factor

Zhao et al. (2008)

ErbB4 (þ)

Guiding signaling

Zhao et al. (2008)

CXCR4 (þ)

Guiding signaling

Zhao et al. (2008)

CXCR7 (þ)

Guiding signaling

Zhao et al. (2008)

Npn1 (þ)

Guiding signaling

You et al. (2005)

Anderson et al. (1997) and Cobos et al. (2007)

Alifragis et al. (2004) and Liodis et al. (2007)

Kanatani et al. (2008)

Continued

the misspecification of cortical VZ progenitors, some cells abnormally tangentially migrate from the cortex into the GE (green and orange dashed arrows) (Chapouton et al., 2001). (c) Nkx2.1 is required for normal MGE development (Butt et al., 2008; Du et al., 2008; Flandin et al., 2010; Sussel et al., 1999; Xu et al., 2004, 2010). In Nkx2.1-deficient brain, the LGE is larger at the expense of misspecified MGE (red stripes), resulting in strong reduction of MGE-derived cortical interneurons subtypes and a failure of interneurons to invade the striatum (St) territory (Butt et al., 2008; Flandin et al., 2010; Sussel et al., 1999). Neuropilin-1 (Nrp1) and Neuropilin-2 (Nrp2), the receptors for the striatal repulsive molecules Semaphorin-3A (Sema3A) and Semaphorin-3F (Sema3F), respectively, are expressed by MGE-derived cortical and absent from MGE-derived striatal interneurons, mediating thereby the segregation of these populations (Marin et al., 2001). Semaphorins repel Nrp1- and Nrp2-expressing cells destined for the neocortex. By contrast, Nkx2.1 specifically maintained in MGE-derived striatal interneurons acts cell-autonomously to allow their migration to the striatum by negatively regulating their responsiveness to class III semaphorins through a direct inhibition of Nrp2 expression (Marin et al., 2001; No´brega-Pereira et al., 2008). (d) When Nkx2.1 is conditionally inactivated in postmitotic MGE-derived migrating interneurons, cortical interneurons can reach their target territory, in contrast to striatal interneurons that strongly misexpress Nrp2 receptor and abnormally respond to striatal class III semaphorin repulsion. (e) By contrast, Nkx2.1-overexpressing neurons migrating from MGE cannot maintain Nrp2 expression and are unresponsive to Sema3A/F-mediated repulsion, compromising migration of MGE-derived cortical interneurons that accumulate in the basal ganglia (No´brega-Pereira et al., 2008).

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TABLE 21.1 Bibliographical References Illustrating the Implication of Several TFs in the Control of Either Radial and/or Tangential Migration in the Telencephalon—cont’d Transcription factor

Radial migration

Tangential migration

Transcriptional target

References

Pax6

Caric´ et al. (1997)

Brunjes et al. (1998), and Nomura et al. (2006), and Gopal et al. (2008)

Arx (þ)

Transcription factor

Visel et al. (2007)

Er81 (þ)

Transcription factor

Tuoc and Stoykova (2008)

EphrinA5 (þ)

Guiding signaling

Nomura et al. (2006)

Sema3C

Guiding signaling

Mattar et al. (2004)

EphA5

Guiding signaling

Mattar et al. (2004)

Ngn1/Ngn2

Brn1/Brn2

ARX

Hand et al. (2005), Ge et al. (2006), and Heng et al. (2008)

McEvilly et al. (2002), and Sugitani et al. (2002)

Colombo et al. (2007), and Friocourt et al. (2008)

Kitamura et al. (2002), Colombo et al. (2007), and Friocourt et al. (2008)

Dcc (þ)

Guiding signaling

Mattar et al. (2004)

SrGap3 (þ/ )

Guiding signaling

Mattar et al. (2004)

Tbr1/Tbr2

Transcription factor

Englund et al. (2005)

NeuroD1 NeuroD2 (þ)

Transcription factor

Hevner et al. (2006) and Roybon et al. (2010)

p35/Cdk5 subunit (þ)

Cytoskeletal regulator

Ge et al. (2006)

Dcx (þ)

Cytoskeletal regulator

Ge et al. (2006)

RhoA ()

Cytoskeletal regulator

Ge et al. (2006)

Rnd2 (þ)

Cytoskeletal regulator

Heng et al. (2008)

p35/Cdk5 subunit (þ)

Cytoskeletal regulator

McEvilly et al. (2002)

Dab1()

Guiding signaling

McEvilly et al. (2002), and Sugitani et al. (2002)

Cdh8 (þ)

Guiding signaling

Fulp et al. (2008)

Cxcr4 (þ)

Guiding signaling

Fulp et al. (2008)

The transcriptional targets susceptible to mediate their function during migration are also listed, namely, other TFs, guidance and cytosqueletal regulators; þ or – signs respectively indicate upregulation or downregulation of expression levels, respectively; underlined names indicate direct targets.

Several challenges still attend the pursuit of a full understanding of the molecular processes governing tangential migration. While decisions about neuronal fate are taken in the progenitor cell, therefore impinging on whether to migrate tangentially or radially, the directionality of migration must be constantly regulated in relation to the available environmental guiding cues. These processes have to be coupled to the maintenance of neuronal polarity in the migratory mode, while at the same time allowing for dynamic morphological

changes of the cell during progression. In addition, during tangential migration, the axonal leading process and cell body may either be coordinated or respond differently to environmental cues and be guided independently to their target territory. For instance, in FBM neurons, the movement of the cell body can be completely dissociated from the axonal leading process growth, whereas in PN, the nucleus tangentially migrate by translocation into a short axonal leading process until they reach the ventral r4, where these movements are

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21.3 CONCLUSIONS AND PERSPECTIVES

dissociated, while the axon progresses to the cerebellum (Kawauchi et al., 2006). This raises the question of the coordination of migratory and axon guidance programs in individual cells (Butler and Tear, 2007; Polleux et al., 2007; Shirasaki and Pfaff, 2002). Moreover, growth of the dendritic arbors generally only occurs after the cell body reaches its final position. Thus, distinct transcriptional programs may independently control these processes and/or they may rely on posttranscriptional events. Other programs may be intrinsically repressing further steps of the differentiation program to allow migration. For instance, in migrating cortical interneurons, Dlx1 and Dlx2 repress the expression of genes involved in axonal growth, synaptogenesis, and axon or dendritic branching (Cobos et al., 2007). Another essential question for which the information is currently sparse concerns the contribution of transcriptional mechanisms to control the coordination and transition between tangential and radial migration in the vertebrate hindbrain. Once they reach their target location, tangentially migrating neurons switch from tangential to radial migration mode, enter into the brain and nucleate. Results concerning the cortical interneurons suggest that change in TF program and downstream effectors may regulate the transition between these two types of migrations, which require distinct as well as partially overlapping molecular machineries (Che´dotal and Rijli, 2009 for review). Thus, it is currently difficult to imagine how such complex events could be simultaneously regulated and integrated in the cell nucleus, and the answer to this challenging question lies ahead. However, recent advances have hinted that epigenetic modifications directly influence the transcriptional state of the chromatin (Collas et al., 2007; Hirabayashi and Gotoh, 2010; Simon and Kingston, 2009). Such mechanisms could impact the transitions between neuronal specification, migration, and progression into the differentiation program, potentially also linking transcriptional programs to the response of the cell to morphogen signaling and environmental cues. For example, Polycomb-mediated epigenetic repression and retinoic-acid-mediated activation play important roles for the establishment and maintenance of the nested Hox expression patterns in the neuroectoderm of the early vertebrate embryo (Gieni and Hendzel, 2009; Glover et al., 2006; Soshnikova and Duboule, 2009). It is currently not known whether such a regulatory system also works to maintain the Hox patterns in RL progenitors and postmitotic tangentially migrating neurons. Moreover, contextdependent modifications of chromatin condensation could also modulate TF activity through modification of the accessibility of their potential targets. In this respect, the activation of neuronal migration requires a global condensation of the chromatin triggered by general changes of its epigenetic profile (Gerlitz and Bustin, 2010), paving

397

the way for the exploration of epigenetic regulation of neuronal tangential migration.

Acknowledgments Work in the FMR laboratory is supported by the Swiss National Science Foundation (CRSI33_127440), ARSEP, and the Novartis Research Foundation. T. Di Meglio is recipient of an EMBO Long-Term postdoctoral fellowship.

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