Instituto de Neurociencias-CSIC, Universidad Miguel Hernández, Campus de San Juan, Apartado 18, 03550 San Juan de Alicante, Spain
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Abstract |
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Key Words: calcium signalling, cytoskeleton, gabaergic neurons, neuronal migration, -tubulin
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Introduction |
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Most GABA-ergic interneurons of the cortex originate in the ganglionic eminences of the basal telencephalon (De Carlos et al., 1996; Tamamaki et al., 1997
; Anderson et al., 1999
; Wichterle et al., 2001
; Marin and Rubenstein, 2001
). After leaving the proliferative zone in the MGE, they migrate following tangential pathways in different cortical compartments: the subventricular zone (SVZ), the intermediate zone (IZ) and the marginal zone (MZ). It is assumed that interneurons migrate by nucleokinesis as they traverse the intermediate zone perpendicularly to the radial glial processes, although there is no direct evidence for this. Contact with corticofugal axons at the IZ (Metin et al., 2000
; Denaxa et al., 2001
) hepatocyte growth factor/scatter factor (Powell et al., 2001
) and TrkB signalling (Polleux et al., 2002
) have been proposed to participate in controlling interneuron migration in the developing cerebral cortex. Once in the cortex, tangentially migrating neurons move in a ventricle-directed migration, with a saltatory movement similar to that observed with radially migrating glia-guided neurons originated at the VZ (Nadarajah et al., 2002
; Ang et al., 2003
).
Changes in intracellular calcium plays a central role in numerous developmental processes, included neuronal migration (reviewed in Webb and Miller, 2003). The amplitude and frequency of calcium fluctuations are positively correlated with the rate of granule cell movement in cerebellar microexplant cultures. Interestingly, tonic elevation of [Ca2+]i results in an arrest of cell movement (Komuro and Rakic, 1996
, 1998). In the case of tangentially migrating neurons in the developing cortex, there is no information about the role of calcium changes on cell migration. Tangentially migrating cells express glutamate AMPA receptors as well as GABA-A receptors (Metin et al., 2000
; Poluch and Konig, 2002
) whose activation produces increases in [Ca2+]i (Soria and Valdeolmillos, 2002
). The activation of AMPA receptors in organotypic slice cultures lead to neurite retraction of migrating cells (Poluch et al., 2001
) suggesting a role in tangential migration.
Mutations in several genes affecting nuclear migration in slime molds have suggested a role for cytoplasmic dynein, the dynactin complex and other proteins, such as NUDF and NUDC, in the process of nuclear translocation (Reinsch, 1998; Feng and Walsh, 2001
; Morris, 2003
). In mice and humans, mutations in the ortholog gene of NUDF (LIS1) cause lissencephaly, a brain developmental pathology affecting the process of cortical lamination (Ross and Walsh, 2001
) and a cell-autonomous defect in cell migration (Hirotsune et al., 1998
). In migrating cerebellar granule cells, NudC, Lis1 and cytoplasmic dynein colocalize at the microtubule organizing centre (MTOC) facing the leading pole, in contrast to their widespread distribution in stationary cells, suggesting a functional interaction of these components during neuronal migration in vivo (Aumais et al., 2001
).
We have studied the movement of tangentially migrating cells through the IZ in cortical slice cultures from embryonic (E1314) mouse and in dissociated cell cultures from the MGE. In both experimental conditions, migrating neurons display a characteristic somal translocation or nucleokinetic movement. Nuclear displacement occurs simultaneously or immediately following a local [Ca2+]i increase in the leading process near the nucleus, suggesting that a localized calcium signal is necessary to elicit nucleokinesis.
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Materials and Methods |
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C57 strain mice were mated overnight and vaginal smears examined the next morning. The day of sperm positivity was taken as embryonic day 0.5 (E0.5). Pregnant mice were deeply anaesthetized with chloral hydrate (i.p.) and the fetuses (E13.514.5) extracted by caesarea. Experimental procedures involving live animals were carried out in accordance with the guidelines set by the European Community and were approved by the Animal Care Committee of the authors institution.
Slice Culture
Slices were prepared and cultured as previously described (Soria and Valdeolmillos, 2002). Whole brains were dissected out and embedded in warm (41°C) 4% low-melting point agarose (Sigma, St Louis, MO) and rapidly cooled. Coronal cortical slices 300 µm thick were cut with a Vibratome (VT1000S; Leica, Germany). Caudal sections were used in which both the medial ganglionic eminence (MGE) and lateral ganglionic eminence (LGE) were present. The slices were cultured on top of Millicell membranes (Millipore, Bedford, MA) of 0.4 µm pore diameter in Neurobasal medium (Life Technologies Gaithersburg, MD) supplemented with B27 (1:50; Life Technologies), 6.5 mg/ml glucose, 0.1 mM glutamine and 50 mg/ml penicillin/streptomycin for periods ranging from 24 to 48 h. We used confocal Oregon-green BAPTA microfluorescence for the analysis of nuclear movements and [Ca2+]i measurements. Experiments were carried out on slices at 2326°C continuously superfused (1 ml/min) in ACSF medium. For the experiments described in this study, 75 slices from 45 animals were pro-cessed.
Time-lapse Experiments
Cortical slices were removed from the culture medium and incubated for 1 h in Neurobasal medium containing 10 µM Oregon-green BAPTA AM (Molecular Probes, Eugene, OR), dissolved in 0.09% dimethyl sulfoxide and 0.006% pluronic acid. In some experiments we used Fluo-3 as a calcium indicator with essentially the same results. Slices were transferred to the stage of an upright Leica DMLFSA microscope coupled to a confocal spectral scanning head (Leica TCS SL) and viewed through 1060x water immersion objectives. Oregon-green BAPTA labeling was excited with the 488 nm line of an argon laser and the fluorescence emitted between 500 and 540 nm measured via a photomultiplier tube. We recorded XYZ stacks of images at a frequency of one stack every 13 min for periods of up to 60 min. To analyze cell movement, z projection images of every stack were projected in a single image, that we call XYZt projection. This image represents a two-dimensional history of a given cell within a region (see for example the XYZt image in Fig. 2). With this procedure it is immediately obvious when a cell moves with respect to another. To avoid photodamage of the slice and photo bleaching of the indicator, laser excitation was keep to the minimum compatible with a good signal to noise ratio. Changes in Oregon-green fluorescence are expressed as the ratio between fluorescence at the beginning of the experiment and at a given time-point. Drugs were micro-perfused from a patch pipette positioned above the cell of interest by pressure injection of pulses of 100 ms duration. The indicated concentration of the drugs refers to those in the pipette solution.
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Dissociated MGE Cells
Fetuses (E13.5) were decapitated and heads immediately placed in chilled L15 medium. Brains were isolated and the MGE dissected in L15 medium and transferred to DMEM supplemented with N2 in which cells were dissociated by five gentle passages through a pipette tip. Cells dissociated from one brain were resuspended in 1 ml of medium and plated on glass coverslips treated with polylysine (mol. wt 70150 000 at 0.01%) and laminin (50 µg/ml). Each coverslip received 0.1 ml of the cell suspension and 4 h later 0.9 ml of medium was added to each culture. Cultures were maintained at 37°C in a 5% CO2 atmosphere.
Time-lapse analysis of dissociated cells (2448 h after plating) was performed in an inverted microscope (DMIRB; Leica) while maintaining the culture at 3435°C with continuous superfusion (1 ml/min) in ACSF medium as described above. Cells were incubated 60 min in medium containing Fura-2 AM (5 µM; Molecular Probes, Eugene, OR), dissolved in 0.09% dimethyl sulfoxide and 0.006% pluronic acid. The fluorophore was excited at 350 and 380 nm and the emission at 510 nm recorded with an ORCA C4742 camera (Hamamatsu Photonics). Images were acquired every 1560 s and the fluorescence ratio (F350/F380) calculated using the U7568 software from AQUACOSMOS package.
Immunocytochemistry
Dissociated cells were fixed in a 4% paraformaldehyde solution containing 4% sucrose for 30 min at 37°C. The following antibodies were used in this study: monoclonal anti-gamma-tubulin (GTU88 from SIGMA) at 1/500 dilution revealed with a secondary antibody anti-mouseIgG labelled with Cy2 from Jackson and anti-glutamic acid decarboxylase 6567 (Sigma) at 1/1000 dilution revealed with an anti-rabbit IgG conjugated to Cy3 (Sigma).
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Results |
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Calcium signalling plays a central role in different kinds of cell movement, including neuronal migration (Komuro and Rakic, 1996, 1998), but its role in the tangential migration of interneurons has not been previously explored. We investigated the presence of [Ca2+]i changes during nuclear translocation. The changes in fluorescence intensity shown in Figure 1 already suggest a role for calcium signalling in this process. However, an unequivocal localization of the fluorescence intensity changes with calcium indicators excited at a single wavelength is hindered by the changes in cell morphology during the active phase of movement.
To obtain a better spatial resolution of the [Ca2+]i changes associated with nucleokinesis, we performed additional experiments in dissociated culture of cells from the MGE. Twenty-four hours after plating dissociated neurons show a variety of morphologies including some with bipolar shape (Fig. 3a). Time-lapse sequences of a bipolar cell revealed nucleokinetic movements similar to those described in the slice cultures and characterized by the sliding of the nucleus inside the thicker process. The average speed of nuclear displacement in dissociated cells (Table 1) is about three times faster than that observed in the slices (see Table 11). This difference could be explained as a result of differences in the temperatures (34°C for dissociated cells versus 25°C for the slice cultures) at which time-lapse analyses were performed. Other factors, such as the laminin substratum in which dissociated cells are plated, could also account for these differences.
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This polarized calcium signal suggests the participation of precise mechanisms and structures able to maintain [Ca2+]i asymmetries for prolonged periods of time in highly dynamic cells (Berridge, 1998; Delmas and Brown, 2002
).
Nuclear displacement occurred in isolated cells as well as in cells making contacts with other cells or axonal projections. This observation supports the view that nuclear translocation is an intrinsic property of these cells which can be manifested independently of the guidance contacts used to direct migration within the developing cortex in vivo. Interestingly, cerebellar granule cells follow an intrinsic migratory program, reflected by changes in their migrating behaviors when contact with other cells is absent (Yacubova and Komuro, 2002a).
The microtubular cytoskeleton participate in nucleokinesis (Rivas and Hatten, 1995; Rakic et al., 1996
; Reinsch, 1998
) Dissociated interneurons, visualized as GAD6567 immunopositive cells, showed
-tubulin clearly polarized at one pole of the nucleus. To test whether the polarized distribution of
-tubulin correlated with the leading process, cells showing soma translocation after time lapse experiments were fixed and immunolabelled with anti-GAD6567 and anti-
-tubulin (Fig. 4a). We found that the direction of nuclear movement (toward the right in Fig. 4a) coincided consistently with the diffuse
-tubulin staining pattern, directly demonstrating that microtubules in the leading process are preferentially oriented with their minus ends toward the nucleus. Interestingly,
-tubulin shows a wider distribution in migratory neurons than that observed in multipolar stationary neurons (Fig. 4b) and fibroblasts. A distribution of
-tubulin similar to the one reported here, and colocalizing with LIS1 and Nudel proteins has been described in early differentiating cortical neurons (Feng et al., 2000
).
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A cell with migratory morphology and a branched leading process in the slice (Fig. 5a) was challenged with a brief puff of kainate delivered by a pressure pulse (100 ms duration) through a patch pipette. Fluorescence before, during and after kainate application was measured. Kainate elicited an immediate and transitory [Ca2+]i increase in the soma, the initial part of the leading process and the branches distal to its bifurcation (Fig. 5b) that was not followed by nucleokinesis. The same results were obtained with NMDA and the GABAa agonist muscimol. We also searched for neurotransmitter responses in cells that had displayed nucleokinesis previously (Fig. 5c,d). Kainate also induced a transitory increase in [Ca2+]i in these cells (graph insert), but it was not followed by an immediate movement of the soma. Thirty minutes after kainate stimulation, a slight backward movement (4 µm, see frame at minute 60) was followed by a small forward movement. Other cells in the slice which also showed an increase in [Ca2+]i, did not move in response to kainate. Neurotransmitters play an important role in neuronal migration (Behar et al., 1999, 2001; Simonian and Herbison, 2001
; Ishiuchi et al., 2002
). The lack of a neurotransmitter effect in our observations would suggest that their role in neuronal migration is not directly linked to the nucleokinetic process.
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Discussion |
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Two basic modes of movement, whole cell locomotion and soma translocation, have been described in migrating neurons. Nuclear translocation was first inferred from morphological studies of developing brain (Book and Morest, 1990) and visualized in cerebellar slices (Hager et al., 1995
) and developing cortex (O'Rourke et al., 1992
). Glia-mediated migration of cerebellar neurons involve saltatory phases along the glial processes by translocation of the soma (Gasser and Hatten, 1990
). In cortical slices, movement by whole cell locomotion and by somal translocation, have been described for the radial migration of neurons (Nadarajah et al., 2001
). So both modes of movement presumably represent different phases of cell advancement rather than reflecting cell-type specific or region-specific properties.
The term nucleokinesis was applied first to the nuclear movement observed in bipolar human lung adenocarcinoma cells (Klominek et al., 1991). The nuclei of these cells are transported to the opposite end of the cell, while gross cell shape and position remain unchanged. In slice cultures loaded with the nucleic acid stain SYTO 83 in addition to Oregon-green we found that the cell soma is almost entirely occupied by the nucleus indicating that the observed soma translocations correspond to nuclear displacement (not shown). The sliding of the nucleus changes its shape, from round to fusiform, as it enters the initial part of the leading process. Once the soma translocation is initiated, the movement is steady although the rate of movement is irregular, alternating slow and rapid phases. This migratory dynamic is similar to the one found in the final stages of radially migrating cells as their leading process reaches the marginal zone (Nadarajah et al., 2001
). The main difference would be that radially migrating cells retract their leading process once they reach the marginal zone, while tangentially migrating neurons ought to repeat the same process several times along their migratory route, resulting in a saltatory-like mode of migration.
Likewise, it has been recently shown that GABAergic interneurons migrating tangentially within the marginal zone extend a leading process into the cortical plate where the cell translocates its cell body towards the end of its leading process (Ang et al., 2003). Therefore nucleokinesis seems to be a mechanism widely used by different types of neurons at different developmental stages.
In our recordings we have seen group of cells migrating tangentially arranged in parallel and in some occasions in close contact. However, we have never observed coordinated movements of cells, suggesting that nucleokinesis relays on a mechanism independent for every cell. In fact, nuclear translocation of MGE migrating cells seems to be a cell intrinsic process since it can be observed also in isolated cells in the dissociated cultures.
The effect of neurotransmitters in neuronal migration has been analyzed in different migratory subsets of neurons. In general, it has been found that the effects of the neurotransmitters are very variable, depending on the species and the preparation studied (Komuro and Rakic, 1996, 1998; Fueshko et al., 1998
; Behar et al., 1999
, 2001; Simonian and Herbison, 2001
; Owens and Kriegstein, 2002
; Yacubova and Komuro, 2002b
). In tangentially migrating cells, the activation of glutamate and GABA-A receptors (Metin et al., 2000
; Poluch and Konig, 2002
) increases calcium (Soria and Valdeolmillos, 2002
). The activation of AMPA receptors in organotypic slice cultures lead to neurite retraction of migrating cells (Poluch et al., 2001
) suggesting a role in tangential migration. However, the [Ca2+]i changes elicited by the neurotransmitters were not able to induce nucleokinesis in previously resting cells nor in cells which have shown a previous soma translocation. The lack of a direct effect of neurotransmitters observed here may be reconciled with the above mentioned observations if the role of neurotransmitters in migration is not directly linked to the nucleokinetic process. We have found that during the active phase of nucleokinesis there is a good correlation between the direction of movement and [Ca2+]i polarization (Fig. 3). The fact that a generalized [Ca2+]i increase in cerebellar granule cells does not result in an increase, but rather in a significant decrease in the rate of cell movement (Komuro and Rakic, 1996
) and the results presented here, suggest that the calcium changes associated with the translocation of the soma are spatially and temporarily regulated so that nucleokinesis is activated at the precise place and time.
Migrating granule cells of the cerebellum showed a cage-like distribution of microtubules encircling the nucleus (Rivas and Hatten, 1995) and there are other evidences showing the involvement of microtubules in the process of soma translocation. We hypothesize that the local calcium elevation in the proximal part of the leading process is related to the dynamic modification of cytoskeletal components taking place at this pole of the nucleus. Changes that are reflected also in the wider distribution of
-tubulin observed in migrating neurons as compared to stationary multipolar neurons (Fig. 4b).
In differentiated neurons the cytoskeleton is polarized with axonal microtubules oriented with their plus ends towards the periphery while dendritic microtubules are randomly oriented. Such a polarization is related to the differential distribution of microtubule associated proteins tau and MAP2 predominating in axons and dendrites respectively. However, in migrating cerebellar granule neurons the orientation of Mts does not follow the above mentioned distribution. Thus, the leading processes of migrating granule cells in situ, which will be transformed in dendrites, showed uniform microtubule orientation with their plus ends towards the direction of migration, while microtubules in the trailing process, which will become the axon, are randomly oriented (Rakic et al., 1996). GABA positive cells with bipolar morphology in the developing cortex show a high expression of MAP2 in their leading processes (Tamamaki et al., 1997
; Poluch and Konig, 2002
). Gamma tubulin, a marker of nucleating minus ends of Mts, concentrates in the pole of the nucleus facing the leading process, suggesting that plus ends of microtubules are oriented in the direction of migration in the leading process. Therefore, in contrast with the typical distribution of Mts in differentiated neurons, the orientation of microtubules in migrating cells might reflect the direction of migration rather than their final transformation into axons or dendrites.
The distribution of other proteins implicated in nuclear translocation like LIS1, NUDC and NUDEL, in dissociated cells at early times after plating (Feng et al., 2000) and cerebellar migrating neurons (Aumais et al., 2001
) is similar to the distribution of gamma-tubulin. LIS1-NudE interactions may be crucial for maintaining the dynamic stability of microtubules in migrating neurons and their presence could contribute to the microtubule shortening and translocation of the nucleus in the proximal part of the leading process. The wider distribution of gamma-tubulin we have observed at the leading pole of the nucleus in migrating neurons, suggest that the minus ends of microtubules in the leading process do not nucleate at a single point until LIS1 and NUDEL are sorted to the axon (Sasaki et al., 2000
).
The effect of calcium could be mediated by DCAMKL1, a protein kinase with homology to doublecortin (DCX). DCAMKL1 stimulates polymerization of purified tubulin and contains a domain encoding for a putative Ca2+/calmodulin dependent protein kinase (Lin et al., 2000). CAM kinases are activated downstream of [Ca2+]i transients and phosphorylation of cytoskeletal components such as DCX by DCAMKL1 or other kinases could represent a rapid mechanism for linking calcium signalling to microtubule reorganization.
In conclusion our results directly show that tangentially migrating neurons in the IZ use soma translocation as a mode of migration. Nuclear displacement is associated to a local and sustained [Ca2+]i increase in the leading process near the nucleus, providing a link between internal or external migratory signals and cytoskeletal reorganization.
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Supplementary Information |
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Confocal projection images of a neuron migrating through the IZ. The arrow in the first frame points to the nucleus at the beginning of the sequence. The cell remains in a resting phase during the first half of the sequence, then the nucleus moves, advancing inside the leading process and stops at the end of the sequence. Total recording time was 40 min.
Movie 2. Nucleokinesis and Calcium Changes in Dissociated Cells
Sequential images of Fura-2 fluorescence ratio (pseudo-color coded) superimposed on 380 fluorescence images. During nucleokinesis the maximal [Ca2+]i is located ahead of the nucleus at the initial part of the leading process. This asymmetric distribution of [Ca2+]i is maintained as the nucleus advances. Total recording time was 18 min.
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Notes |
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Address correspondence to Miguel Valdeolmillos, Instituto de Neurociencias-CSIC, Universidad Miguel Hernández, Campus de San Juan, Apartado 18, 03550 San Juan de Alicante, Spain. Email: miguel.valdeolmillos{at}umh.es.
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