1 Max-Planck Institute for Neurobiology, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany
2 IGBMC, Strasbourg, France
*Author for correspondence (e-mail: mgoetz{at}neuro.mpg.de)
Accepted September 28, 2001
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SUMMARY |
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Key words: Cortico-striatal boundary, Pax6, Mash1, Dlx, SFRP2, Mouse
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INTRODUCTION |
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Migrational restriction has also been observed in other parts of the developing CNS, but the mechanisms that regulate cell migration elsewhere in the brain are less well understood (Figdor and Stern, 1993; Fishell et al., 1993; Anderson et al., 1997; Tamamaki et al., 1997). In particular, it is not known how the asymmetry of cell migration between dorsal and ventral regions in the telencephalon is regulated. Here, ventral cells migrate into dorsal regions to a much larger extent than dorsal cells into ventral territories (Fishell et al., 1993; Anderson et al., 1997; Tamamaki et al., 1997; Chapouton et al., 1999; Lavdas et al., 1999; Wichterle et al., 1999; Anderson et al., 2001). A dorsoventral boundary forms at approximately embryonic day (E) 12/13 in the murine telencephalon, separating the dorsally located cortex from the ventrally located ganglionic eminence (GE). Adhesive differences precede the formation of the mechanical boundary formed by a radial glial fascicle (Stoykova et al., 1997; Inoue et al., 2001), similar to the development of boundaries between rhombomeres (Guthrie and Lumsden, 1992; Wizenmann and Lumsden, 1997). The telencephalic radial glial fascicle is often referred to as the cortico-striatal boundary, since it separates the cortex from the lateral part of the GE (LGE) that will later give rise to the striatum (Olsson et al., 1995). Cells in the cortico-striatal boundary express some, but not all, genes characteristic for the dorsal telencephalon and this region has therefore been named ventral pallium (Puelles et al., 2000). However, boundary cells do not express genes characteristic for the ventral telencephalon and the radial glia fascicle forms just above this sharp border of gene expression. The molecular events underlying the biased cell movements across this boundary, with more migration from the GE into the cortex, than from the cortex to the GE, remain largely unknown (Fishell, 1993; Anderson et al., 1997; Chapouton et al., 1999; Neyt et al., 1997; Tamamaki et al., 1997; Lavdas et al., 1999; Wichterle et al., 1999).
Recently it has been demonstrated that the cadherins restrict ventral to dorsal and dorsal to ventral cell movements at early developmental stages prior to boundary formation (Inoue et al., 2001), whereas diffusible factors of unknown nature seem to restrict the movements of cortical cells at later stages of development (Neyt et al., 1997). Furthermore, in the absence of Pax6, a paired-homeodomain transcription factor that is normally expressed in the cortex, cell migration from the GE into the cortex is strongly enhanced, whereas migration from the cortex into the GE is affected much less (Chapouton et al., 1999). Patterning of the telencephalon is, however, severely distorted in the absence of Pax6 (Stoykova et al., 2000). For example, the expression domains of the basic helix-loop-helix (bHLH) transcription factors neurogenin 1 (ngn1; also known as Neurod3), ngn2 (also known as Atoh4; atonal homolog 4) and Mash1 (Ascl1) are completely changed (Stoykova et al., 2000; Toresson et al., 2000). In the developing telencephalon, Mash1 and ngn2 are expressed in a defined dorsoventral pattern, with Mash1 expressed at high levels in the developing GE and ngn1/2 restricted to the developing cortex (Gradwohl et al., 1996; Ma et al., 1997), consistent with a role for these genes in specifying region-specific phenotypes, such as the migratory behavior of neurons (Gradwohl et al., 1996; Ma et al., 1997; Casarosa et al., 1999; Fode et al., 2000). In the absence of ngn2, Mash1 is upregulated in the cortex while most other ventral transcription factors do not expand into the cortex (Fode et al., 2000). Therefore in this study we have examined whether the loss of ngn2 and acquisition of Mash1 allows the spread of cortical cells into ventral regions.
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MATERIALS AND METHODS |
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X-gal histochemistry and in situ hybridization
Telencephalic slices were cut frontally (300 µm thick with a tissue chopper (McIllwain) or 100 µm thick with a vibratome (Campden), fixed in 0.5% glutaraldehyde and stained following standard protocols. For the combination with in situ hybridization, telencephali were fixed in 4% paraformaldehyde (PFA) for 1.5 hours at 4°C, cryoprotected and 12 µm sections were cut using a cryostat and stained as described by Houzelstein and Tajbakshs (Houzelstein and Tajbakshs, 1999). Digoxigenin-labeled RNA probes were made by in vitro transcription using the NTP labeling mix from Roche and T3, T7 or SP6 polymerase from Stratagene. The following RNA probes were used: lacZ (A. Stoykova, F. Cecconi, MPI of Biophysical Chemistry, Göttingen, Germany), ngn2 (Gradwohl et al., 1996), Math2 (Bartholomä and Nave, 1994), Pax6 (Stoykova et al., 1996), R-cadherin (Cdh4) (Mastunami and Takeichi, 1995), cadherin 6 and 11 (Cdh6, Cdh11) (Inoue et al., 2001) (M.Takeichi, University of Kyoto, Japan); cadherin 8 (Cdh8) (Korematsu and Redies, 1997); Slit1, Slit2, Slit3, Robo1, Robo2 (Y. Rao, Washington University School of Medicine, St. Louis, MI, USA; A. Chédotal, Hopital de la Salpetriere, Paris, France), Tenascin C (Götz et al., 1997), Wnt7b (A. McMahon, Harvard University, Cambridge, MA, USA), SFRP2 (Kim et al., 2001), Dlx1, Dlx5, Mash1 (Casarosa et al., 1999; Toresson et al., 2000), ephrin A5 and EphA5 (L. Lindemann, FMI, Basel, Switzerland), ephrin B1, B2, B3 (R. Klein, MPI of Neurobiology, Martinsried, Germany), EphA3 (P. C. own construction). In situ hybridizations were performed as described previously (Cau et al., 1997).
Immunohistochemistry
Brains were fixed and sectioned as described above. Sections were incubated in primary antisera over night at 4°C and fluorescently tagged secondary antisera for 45 minutes at room temperature as described by Hartfuss et al. (Hartfuss et al., 2001). The RC2 antiserum was used 1:500 (mouse IgM, P. Leprince, University of Liège, Belgium), antiserum against BLBP 1:5000 (polyclonal rabbit, N. Heintz, Rockefeller University, New York, USA) and the monoclonal 9-4 antiserum 1:10 (T. Hirata, Kyoto University, Japan). Sections were analyzed using a Zeiss Axiophot or Leitz confocal microscope.
Migration assay and transplantations
300 µm thick slices of E14 telencephali were cut with a tissue chopper, injected focally with EGFP adenovirus and cultured in millicell-CM inserts (Millipore) in DMEM with 10% FCS (Chapouton et al., 1999). Photos of the slices were taken 24 hours and 45 hours after injection. Slices were prepared from individual embryos that were genotyped thereafter. Migration analysis was performed blind and the genotype was revealed only after the number of migrating cells had been analyzed. Data is expressed as ± s.e.m. In transplantation experiments a small piece (about 300x300 µm) of cortex from the EGFP mice (Okabe et al., 1997) was laid onto a host slice (from ngn2lacZ-crosses) and cultured for 24 hours. After fixation in 4% PFA slices were examined using the confocal microscope.
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RESULTS |
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If the ectopic cells in the GE were due to migrational spread from the cortex, one might expect their accumulation over time. We therefore analyzed ngn2lacZ mice three days later, at E17, and observed twice as many ectopic cells in the GE (95±19 cells per section, n=10) than at E14 (50±19 cells per section, n=10). Interestingly, cells had spread deeper into the GE at E17 than at E14 and ectopic cells were also located in the ventricular zone of the GE at E17 where no cells were detected at E14 (Fig. 1F). Indeed, an additional hint for an unusual cell migration from the cortex into the GE in the ngn2lacZ/ngn2lacZ mice is that many ß-galactosidase-positive cells in GE exhibit the morphology of migrating cells, with an elongated cell body and a leading process (Fig. 1G).
Dorsoventral cell migration from the cortex into the GE in homozygous ngn2lacZ mice
To directly examine if the loss of ngn2 function affects cell migration, we used a previously established assay involving the focal injection of an EGFP-expressing adenovirus into telencephalic slices (Chapouton et al., 1999). Cortical slices (300 µm) from E14 wild-type and ngn2 mutant littermates were infected close to the cortico-striatal border with an EGFP-adenovirus as depicted in Fig. 2. Note that the sulcus between the cortex and GE allows the identification of the dorsoventral boundary for more than 2 days in vitro (Chapouton et al., 1999). As observed previously (Chapouton et al., 1999), few cells infected in the cortex of E14 wild-type mice crossed the boundary into the GE, 18 or 45 hours post-infection (Fig. 2A), with ectopic cells found in the GE of only 17% of slices and a mean number of 0.3 cells crossing the border per slice (Table 1). In contrast, many labeled cells were observed to migrate within the cortex, confirming that infected cells retained their migratory capacity (Fig. 2A).
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We also examined whether the boundary in the ngn2 mutant telencephalon is more permeable to cells from the GE, by injecting EGFP-adenovirus in the GE of E14 wild-type and ngn2/ telencephalic slices. As previously observed, GE cells migrate into the cortex much more frequently than cortical cells migrate into the GE (Tamamaki et al., 1997; Anderson et al., 1997; Chapouton et al., 1999; Lavdas et al., 1999; Wichterle et al., 1999; Anderson et al., 2001). In most of the injected slices (79%), cells from the GE had migrated into the cortex 2 days after labeling and no difference was detected in telencephalic slices from homozygous ngn2 mutants (GE cells migrated into the cortex in 89% of slices, see Table 2). Thus, the absence of ngn2 does not affect cell migration from the GE into the cortex, but only from the cortex into the GE.
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Non cell-autonomous effects on cell migration in ngn2/ telencephalon
If these alterations in the cortico-striatal boundary were significant, wild-type cells should also be affected in their migration across a ngn2/ telencephalic border. To test this idea, we used an in vitro transplantation approach and transplanted small pieces of cortex or GE from green mice, a transgenic line that expresses EGFP ubiquitously in all cells (Okabe et al., 1997), onto slices of ngn2/ or wild-type telencephali. We first verified that the normal migrational properties at the corticostriatal boundary were maintained in this transplantation assay by putting small pieces of green GE (E14) onto a slice of the GE from a wild-type telencephalon (E14). A mean of 96.2±3.2 green cells per slice (n=4) migrated from the GE into the cortex during 1 day in vitro. In contrast, when pieces of green mouse cortex of comparable size were transplanted onto the cortex of slices from E14 wild-type telencephalon, only very few green cells crossed into the GE (5.5±1.2 green cells in the GE/slice, n=42). This experimental paradigm thus respects the typical asymmetrical restriction at the cortico-striatal boundary.
When we transplanted pieces of green fluorescent cortex onto the cortex of slices from ngn2/ telencephalon (Fig. 4A) we observed a clear increase in the number of cortical cells crossing into the GE compared to transplants placed on slices from wild-type littermates. While on a wild-type cortex a mean number of 2.9±1 (n=12) green cortical cells had entered the GE after 1 day in vitro, more than five times as many cells (16.3±5; n=12) had crossed the boundary on a ngn2/ substratum. Thus, wild-type cortical cells spread to a larger extent into the GE on a ngn2/ versus a wild-type substratum (Table 3). Two possible mechanisms could lead to this result: first, migration is enhanced on the ngn2/ telencephalon, or, second, the mutant boundary is more permissive for cortical cells to enter the GE. Indeed, a higher number of cells migrated out of transplants placed on ngn2/ telencephalic slices compared to wild-type slices (1.6-fold increase; Fig. 4B; Table 3), suggesting that the mutant cortex is a more permissive substratum for migration than the wild-type cortex. Nevertheless, taking this difference into account by normalizing the proportion of cells entering the GE to the total number of migrating cells, there were still more cells crossing the boundary on a mutant substratum (3.7%±0.7%) than on a wild-type substratum (1.2%±0.5%; Fig. 4C; 3 fold increase on ngn2/ substratum; Table 3). This suggests that the boundary between the cortex and the GE has become more permissive for cortical cells in the absence of ngn2 and that the loss of ngn2 is not required in the migrating cells since wild-type cells also react to the substratum changes of ngn2/ slices.
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DISCUSSION |
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Distinct migrational restriction of cells from the cortex and GE
Migration of cells from the GE into the cortex has recently gained a lot of attention, since it is thought that these cells are the source of most interneurons in the cortex (Anderson et al., 1997; Anderson et al., 2001; Pleasure et al., 2001). Analysis of mouse mutants and in vitro experiments have revealed several molecules that are required for, or act positively on, this ventrodorsal cell migration [Dlx1 and 2 (Anderson et al., 1997); Nkx2.1 (Sussel et al., 1999); Mash1 (Casarosa et al., 1999); Slit (Zhu et al., 1999); HGF (Powell et al., 2001)]. In contrast, the strict confinement of cortical cells in their territory is much less understood. There are two general possibilities of how such a selective restriction of cells on the two different sides of the boundary could be achieved. Either, dorsal and ventral cells react differently to the same inhibitory cues in the boundary, or the boundary region contains distinct cues restricting selectively dorsal or ventral cells. Our data favor the latter possibility for the following reasons.
The loss of Ngn2 affects only the migration of cortical cells, but not of GE cells. This is concluded from our migration analysis using focal injections of EGFP adenovirus into the GE or the cortex in telencephalic slices. In ngn2/ slices more cortical cells migrated into the GE than in wild-type slices, while no difference was detected in the migration of GE cells on wild-type or ngn2/ slices. The number of cortical cells entering the GE in ngn2/ mice was relatively small, but seemingly accumulates with time. Within 3 days the number of ectopic lacZ-positive cells in the GE of ngn2/ mice doubled. Moreover, ectopic cells were found at more ventral positions than at earlier stages, suggesting that they continue to migrate during this period. Consistent with the formation of the boundary at E12/13, we observed the earliest ectopic cells around this time in the ngn2/ mice (data not shown), suggesting that the number of ectopic cells observed at E14 is already the result of about 2 days accumulated migration. Thus, a relatively small leakage of cells from the cortex across the boundary may result in a considerable number of ectopic cells during development.
Ngn2 is expressed in the cortex, but not in the GE (Gradwohl et al., 1996; Ma et al., 1997; Fode et al., 2000). The loss-of-function condition of Ngn2 could therefore result in either cell autonomous defects of cortical cells, e.g. by regulation of receptor molecules on the migrating cells, or in non cell-autonomous defects of properties of the migration substratum in the cortex and/or the boundary region. We have two sets of evidence that favor the latter interpretation, but do not exclude the former. First, the radial glial fascicle forming the cortico-striatal boundary is less fasciculated in the ngn2/ telencephalon compared to wild type, and expression of SFRP2, the molecular marker of this boundary region, is expanded. While these changes are very subtle, they are clearly non cell-autonomous and relevant for migrating cells as demonstrated in our in vitro transplantation experiments. Thus, Ngn2 regulates specific features of the cortico-striatal boundary required for the tight restriction of cortical cells. Cells from the GE, however, do not recognize these changes since their migration into the cortex is not affected. Thus, the molecules regulated by Ngn2 in the boundary affect only the restriction of cortical, but not striatal cells. This feature obviously distinguishes the telencephalic border from rhombomere boundaries where the same molecules are responsible to restrict cells on both sides of the boundary (Mellitzer et al., 1999; Xu et al., 1999). A prominent boundary in the diencephalon, the zona limitans also shows unique features (Zeltser et al., 2001), suggesting that boundary structures are highly specialized in different brain regions.
Comparison of tangential migration in Pax6 and ngn2 mutant mice
Our previous analysis of cell migration in the Pax6 mutant mice Small eye (Chapouton et al., 1999) showed a prominent increase in ventrodorsal and a weaker effect on dorsoventral cell migration. The latter is comparable in its extent to the effect seen in the ngn2-deficient mice analyzed in this study. Indeed, ngn2 is also down regulated in the cortex and spinal cord of Pax6 mutant mice (Stoykova et al., 2000; Scardigli et al., 2001), consistent with a similar effect on cortical cell migration in both mutants. In addition, the loss of Pax6 function affects the restriction of cells from the GE, while ngn2 does not. Thus, molecular changes present in the Pax6/ telencephalon, but absent in the ngn2/ mice should specifically affect GE cell migration, while changes present in both mutants are likely involved in the defects in cortical migration.
Indeed, the Pax6 mutant mice exhibit more pronounced changes within the cortex and the boundary than ngn2/ mice. For example, the entire boundary structures are lost at the cellular and molecular (TN-C, SFRP2) level in the Pax6 mutant Small eye (Stoykova et al., 1997; Chapouton et al., 1999; Kim et al., 2001). Furthermore, R-cadherin, Wnt7b, Slit2 and ephrin B2 expression are down-regulated in the cortex of the Pax6 mutant (P. C. and M. G., unpublished observations) (Stoykova et al., 1997; Kim et al., 2001), while these molecules are not affected in the ngn2/ telencephalon, with the exception of the broader SFRP2 expression domain. Besides cell surface or extracellular signaling molecules, the expression of transcription factors changes dramatically in the Pax6 mutant cortex. In particular, gene expression normally restricted to the ventral telencephalon, such as Dlx1, Mash1 and Gsh2, spreads into the cortex in the Pax6 mutants (Stoykova et al., 1996; Stoykova et al., 2000; Toresson et al., 2000; Yun et al., 2001). Obviously this ventralization might endow cortical cells with ventral cell surface properties allowing the mixing of cortical with striatal cells (Stoykova et al., 1997; Chapouton et al., 1999). Similarly, Mash1, Dlx1, Dlx5 and GAD67 are up regulated ectopically in the cortex of ngn2/ mice (Fode et al., 2000). However, GAD67, Dlx1 and Dlx5 are ectopically expressed only in medial cortical regions and hence could not affect cells close to the cortico-striatal boundary (Fode et al., 2000). In contrast, Mash1 is expressed throughout the cortex in precursor cells and hence could mediate cortical cells acquiring ventral cell surface identities allowing them to mix with GE cells. To test this hypothesis, we examined ß-gal-positive cells in ngn2;Mash1 double mutants (Fode et al., 2000; Nieto et al., 2001). Ectopic ß-gal-positive cells in the GE also occurred in ngn2/ and ngn2;Mash1 mutants, suggesting that the ectopic expression of Mash1 in the cortex is not required for the spread of cortical cells into the GE in the absence of Ngn2. Thus, the loss of Ngn2 is sufficient to cause a leakage of cortical cells into the GE, consistent with the suggestion that Pax6 might regulate the cues responsible for the restriction of cortical cells in their territory via Ngn2.
Fate change of ngn2 mutant cortical cells in the GE
The tight delineation of adjacent brain regions avoids the leakage of cells from one territory into the other. Such a leakage would result in a foreign cell population in the adjacent brain region with the danger of these cells differentiating into neurons with the wrong physiological properties. An example is the cortex of Pax6 mutant mice, which contains a significantly higher number of GABAergic cells due to the increased invasion by this cell type from ventral positions (Chapouton et al., 1999). The tight balance between excitatory neurons that originate mostly in the cortex and inhibitory GABAergic neurons of ventral origin is crucial for the appropriate functioning of the cortex (Roberts et al., 1995; Götz, 2001). Since there is always a small amount of leakage at boundaries between brain regions (Birgbauer and Fraser, 1994; Chapouton et al., 1999; Hamasaki et al., 2001), an additional mechanism has to re-adjust the fate of the few cells entering the neighboring region. Gurdon (Gurdon, 1988) coined the term community effect to describe the influence that cellular majorities have on the fate of cellular minorities [see also Götz (Götz, 1995)]. Indeed, cells from odd-numbered rhombomeres change their fate when they enter even-numbered rhombomeres (Xu et al., 1995), as do transplanted cells (Fishell, 1995; Campbell et al., 1995; Olsson et al., 1997) [however see Na et al. (Na et al., 1998)]. Unfortunately, few of these transplantation studies examined whether regulation of region-specific transcription factors is a prerequisite for such fate changes (Na et al., 1998).
The ectopic cells originating in the cortex and entering the GE in the ngn2/ telencephalon therefore provided a unique opportunity to examine the regulation of transcription factors characteristic of the dorsal or ventral regions in the telencephalon. This analysis clearly revealed that ß-gal-positive cells still have a dorsal identity in the cortex but change to a ventral identity after entering the GE. ß-gal-positive cells expressed ngn2-lacZ, Pax6, R-cadherin, Math2 and Mash1 in the ngn2/ cortex. When they entered the GE, however, they down-regulated expression of most of these genes, characteristic of the cortex, and acquired instead expression of Dlx5, characteristic of the ventral telencephalon. Taken together, these data seem to argue against the possibility that dorsal cells acquire a ventral identity already in the cortex allowing them to enter the GE. Rather, ß-gal-positive cells within the cortex express dorsal and no ventral genes (except Mash1) while they turn off dorsal genes and acquire a ventral phenotype only after they have migrated for some distance into the GE. In order to reveal the identity of molecules essential in mediating the fate change of ectopic cortical cells, ngn2/ mice could be crossed with mice deficient for key patterning genes in the GE.
These results also suggest a further level of asymmetry between dorsal and ventral cells in the developing telencephalon. While most cells entering the cortex from the GE seem to maintain their specification as ventral cells and continue to express Lhx6, Dlx1/5 and GAD67 (Anderson et al., 1997; Anderson et al., 2001; Lavdas et al., 1999; Pleasure et al., 2001), cortical cells entering into the GE seem to change their fate. Interestingly, Hamasaki et al. (Hamasaki et al., 2001) detected a population of cells, generated at early stages in the piriform cortex, migrating into the developing striatum. This population is eliminated by cell death at later stages, a second mechanism eliminating inappropriate types of neurons. Thus, not only migrational restriction, but also the mechanisms instructing fate changes seem to act asymmetrically on ventral and dorsal cells in the developing telencephalon.
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ACKNOWLEDGMENTS |
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REFERENCES |
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Anderson, S. A., Eisenstat, D. D., Shi, L. and Rubenstein, J. L. R. (1997). Interneuron migration from basal forebrain to neocortex: dependence on DIx genes. Science 278, 474-476.
Anderson, S. A., Marín, O., Horn, C., Jennings, K. and Rubenstein, J. L. R. (2001). Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353-363.
Bartholomä, A. and Nave, K.-A. (1994). NEX-1: A novel brain specific helix-loop-helix protein with autoregulation and sustained expression in mature cortical neurons. Mech. Dev. 48, 217-228.[Medline]
Birgbauer, E. and Fraser, S. E. (1994). Violation of cell lineage restriction compartments in the chick hindbrain. Development 120, 1347-1356.
Bulfone, A., Puelles, L., Porteus, M. H., Frohman, M. A., Martin, G. R. and Rubenstein, J. L. (1993). Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. J. Neurosci. 13, 3155-3172.[Abstract]
Campbell, K., Olsson, M. and Björklund, A. (1995). Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 15, 1259-1273.[Medline]
Casarosa, S., Fode, C. and Guillemot, F. (1999). Mash1 regulates neurogenesis in the ventral telencephalon. Development 126, 525-534.
Cau, E., Gradwohl, G., Fode, C. and Guillemot, F. (1997). Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors. Development 124, 1611-1621.
Chapouton, P., Gärtner, A. and Götz, M. (1999). The role of Pax6 in restricting cell migration between developing cortex and basal ganglia. Development 126, 5569-5579.
Edwards, M. A., Yamamoto, M. and Caviness, V. S., Jr (1990). Organisation of radial glia and related cells in the developing murine CNS. An analysis based upon a new monoclonal antibody marker. Neuroscience 36, 121-144.[Medline]
Figdor, M. C. and Stern, C. D. (1993). Segmental organisation of embryonic diencephalon. Nature 363, 630-634.[Medline]
Fishell, G. (1995). Striatal precursors adopt cortical identities in response to local cues. Development 121, 803-812.
Fishell, G., Mason, C. A. and Hatten, M. E. (1993) Dispersion of neural progenitors within the germinal zones of the forebrain. Nature 362, 636-638.[Medline]
Fode, C., Ma, Q., Casarosa, S., Ang, S.-L., Anderson, D. J. and Guillemot, F. (2000). A role for neural determination genes in specifying the dorsoventral identity of telencepalic neurons. Genes Dev. 14, 67-80.
Fraser, S., Keynes, R. and Lumsden, A. (1990). Segmentation in the chick embryo hindbrain is defined by cell lineage districtions. Nature 344, 431-435.[Medline]
Götz, M. (1995). Getting there and being there in the cerebral cortex. Experientia 5, 359-369.
Götz, M. (2001). Glial cells generate neurons: implications for neurospychiatric disorders. Disorders of Brain and Mind II, Ed.: M.Ron. Cambridge University Press.
Götz, M., Wizenmann, A., Reinhard, S., Lumsden, A. and Price, J. (1996). Selective adhesion of cells from different telencephalic regions. Neuron 16, 551-564.[Medline]
Götz, M., Bolz, J., Joester, A. and Faissner, A. (1997). Tenascin-C synthesis and influence on axonal growth during rat cortical development. Eur. J. Neurosci. 9, 496-506.[Medline]
Gurdon, J. B. (1988). A community effect in animal development. Nature 336, 772-774.[Medline]
Guthrie, S. and Lumsden, A. (1992). Formation and regeneration of rhombomere boundaries in the developing chick hindbrain. Development 112, 221-229.[Abstract]
Gradwohl, G., Fode, C. and Guillemot, F. (1996). Restricted expression of a novel murine atonal-related bHLH protein in indifferentiated neural precursors. Dev. Biol. 180, 227-241.[Medline]
Hamasaki, T., Goto, S., Nishikawa, S. and Ushio, Y. (2001). Early-generated preplate neurons in the developing telencephalon: Inward migration into the developing striatum. Cerebral Cortex 11, 474-484.
Hartfuss, E., Galli, R., Heins, N. and Götz, M. (2001). Characterization of CNS precursor types and radial glia. Dev. Biol. 229, 15-30.[Medline]
Houzelstein, D. and Tajbakhsh, S. (1999). Increased in situ hybridization sensitivity using non-radioactive probes after staining for ß-galactosidase activity. Technical Tips Online: 1:57:T01600.
Inoue, T., Tanaka, T., Takeichi, M., Chisaka, O., Nakamura, S. and Osumi, N. (2001). Role of cadherins in maintaining the compartment boundary between the cortex and striatum during development. Development 128, 561-569.
Kim, A. S., Anderson, S. A., Rubenstein, J. L., Lowenstein, D. H. and Pleasure, S. J. (2001). Pax-6 regulates expression of SFRP-2 and Wnt-7b in the developing CNS. J. Neurosci. 21, RC132.[Medline]
Korematsu, K. and Redies, C. (1997). Restricted expression of cadherin-8 in segmental and functional subdivisions of the embryonic mouse brain. Dev. Dyn. 208, 178-189.[Medline]
Lavdas, A. A., Grigoriou, M., Pachnis, V. and Parnavelas, J. G. (1999). The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19, 7881-7888.
Lumsden, A. and Krumlauf, R. (1996). Patterning the vertebrate neuraxis. Science 274, 1109-1114.
Ma, Q., Sommer, L., Cjerjesi, P. and Anderson, D. J. (1997). Mash1 and neurogenin1 expression patterns define complementary domains of neuroepithelium in the developing CNS and are correlated with regions expressing Notch ligands. J. Neurosci. 17, 3644-3652.
Matsunami, H. and Takeichi, M. (1995). Fetal brain subdivisions defined by R- and E-cadherin expressions: evidence for the role of cadherin activity in region-specific, cell-cell adhesion. Dev. Biol. 172, 446-478.
Mellitzer, G., Xu, Q. and Wilkinson, D. G. (1999). Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77-81.[Medline]
Na, E., McCarthy, M., Neyt, C., Lai, E. and Fishell, G. (1998). Telencephalic progenitors maintain anteroposterior identities. Curr. Biol. 8, 987-990.[Medline]
Neyt, C., Welch, M., Langston, A., Kohtz, J. and Fishell, G. (1997). A short-range signal restricts cell movement between telencephalic proliferative zones. J. Neurosci. 17, 9194-9203.
Nieto, M., Schuurmans, C., Britz, O. and Guillemot, F. (2001). Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401-413.[Medline]
Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. and Nishimune, Y. (1997) Green mice as a source of ubiquitous green cells. FEBS Lett. 407, 313-319.[Medline]
Olsson, M., Campbell, K., Wictorin, K. and Björklund, A. (1995). Projection neurons in fetal striatal transplants are predominantly derived from the lateral ganglionic eminence. Neurosci. 69, 1169-1182.[Medline]
Olsson, M., Campbell, K. and Turnbull, D. H. (1997). Specification of mouse telencephalic and mid-hindbrain progenitors following heterotopic ultrasound- guided embryonic transplantation. Neuron 19, 761-772.[Medline]
Pleasure, S. J., Anderson, S., Hevner, R., Bagri, A., Marin, O., Lowenstein, D. H. and Rubenstein, J. L. R. (2001). Cell migration from the ganglionic eminences is required for the development of hippocampal GABAergic interneurons. Neuron 28, 727-740.
Powell, E. M., Mars, W. M. and Levitt, P. (2001). Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Neuron 30, 79-89.[Medline]
Puelles, L., Kuwana, E., Puelles, E., Bulfone, A., Shimamura, K., Keleher, J., Smiga, S. and Rubenstein, J. L. R. (2000). Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6, and Tbr-1. J. Comp. Neurol. 424, 409-438.[Medline]
Roberts, G. W., Royston, M. C. and Götz, M. (1995). Pathology of cortical development and neuropsychiatric disorders. In Development of the Cerebral Cortex. Ciba Foundation Symposium 193 (ed. G. R. Bock and G. Cardew), pp. 296-316. Chichester: Wiley & Sons.
Scardigli, R., Schuurmans, C., Gradwohl, G. and Guillemot, F. (2001). Crossregulation between Neurogenin2 and pathways specifying neuronal identity in the spinal cord. Neuron 31, 203-217.[Medline]
Stoykova, A., Fritsch, R., Walther, C. and Gruss, P. (1996). Forebrain patterning defects in Small eye mutant mice. Development 122, 3453-3465.
Stoykova, A., Götz, M., Gruss, P. and Price, J. (1997). Pax6-dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain. Development 124, 3765-3777.
Stoykova, A., Treichel, D., Hallonet, M. and Gruss, P. (2000). Pax6 modulates the dorso-ventral patterning of the telencephalon. J. Neurosci. 20, 8024-8050.
Sussel, L., Marin, O., Kimura, S. and Rubenstein, J. L. R. (1998). Loss of Nkx2.1 homeobox gene function results in ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 126, 3359-3370.
Tamamaki, N., Fujimori, K. E. and Takauji, R. (1997). Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J. Neurosci. 17, 8313-8323.
Toresson, H., Potter, S. S. and Campbell, K. (2000). Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361-4371.
Wichterle, H., Garcia-Verdugo, J. M., Herrera, D. G. and Alvarez-Buylla, A. (1999). Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nature Neurosci. 2, 461-466.[Medline]
Wizenmann, A. and Lumsden, A. (1997). Segregation of rhombomeres by differential chemoaffinity. Mol. Cell Neurosci. 9, 448-459.
Xu, Q., Alldus, G., Holder, N. and Wilkinson, D. G. (1995). Expression of truncated Sek-1 receptor tyrosine kinase disrupts the segmental restriction of gene expression in the Xenopus and zebrafish hindbrain. Development 121, 4005-4016.
Xu, Q. and Wilkinson, D. G. (1997). Eph-related receptors and their ligands: mediators of contact-dependent cell interactions. J. Mol. Med. 75, 576-586.[Medline]
Xu, Q., Mellitzer, G., Robinson, V. and Wilkinson, D. G. (1999). In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature 399, 267-271.[Medline]
Yun, K., Potter S. and Rubenstein, J. L. R. (2001). Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128, 193-205.
Zeltser, L. M., Larsen, C. W. and Lumsden, A. (2001). A new developmental compartment in the forebrain regulated by lunatic fringe. Nature Neurosci. 4, 683-684.[Medline]
Zhu, Y., Li, H., Zhou, L., Wu, J. Y. and Rao, Y. (1999). Cellular and molecular guidance of GABAergic neuronal migration from an extracortical origin to the neocortex. Neuron 23, 473-485.[Medline]