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First published online December 7, 2008
doi: 10.1242/10.1242/dev.025502
,
,
1 Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones
Científicas and Universidad Miguel Hernández, 03550 Sant Joan
d'Alacant, Spain.
2 Institute of Experimental Medicine, 1083 Budapest, Hungary.
Authors for correspondence (e-mail:
miguel.valdeolmillos{at}umh.es;
o.marin{at}umh.es)
Accepted 22 October 2008
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SUMMARY |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Key words: Cellular dynamics, Chemotaxis, Neuronal migration, Mouse
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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; Lin and Holt,
2007; Round and Stein,
2007). According to this view, growing axons are guided to their
correct targets by steering the growth cone in response to attractive and
repulsive cues (Kalil and Dent,
2005). Given the typical bipolar morphology of many migrating
neurons, with a leading process extending in the way of their migration and a
trailing process in the opposite direction, this model of directional guidance
have also been extensively used to explain the chemotaxis of migrating neurons
(Miyata and Ogawa, 2007;
Noctor et al., 2001;
Rakic, 1990;
Yee et al., 1999). However,
not all migrating neurons have the same morphology. In the developing cerebral
cortex, for example, some migrating interneurons have been described to
exhibit a bipolar morphology with a single leading process
(Jiménez et al., 2002;
Polleux et al., 2002), whereas
many others have been reported to display branched leading processes
(Anderson et al., 1997;
Bellion et al., 2005;
Friocourt et al., 2007;
Kappeler et al., 2006;
Lavdas et al., 1999;
Marín and Rubenstein,
2001; Nasrallah et al.,
2006; Polleux et al.,
2002). The existence of branched leading processes is by no means
specific to cortical interneurons, as other types of tangentially migrating
neurons also adopt this morphology
(López-Bendito et al.,
2006; Marín and
Rubenstein, 2001; Ward et al.,
2005).
The issue that arises in relation to the branched morphology of some
migrating neurons is how they navigate using two leading processes to explore
a wide prospective territory. In the case of cortical interneurons, work over
the past few years has revealed that they originate in the subpallium and
migrate over long distances using multiple tangential pathways
(Corbin et al., 2001;
Marín and Rubenstein,
2001). Moreover, we now know that interneuron migration is
controlled by a complex combination of long-range attractive and repulsive
signals, short-range instructive molecules, cell-adhesion complexes and
motogenic factors (Marín and
Rubenstein, 2003; Métin
et al., 2006). With the exception of nucleokinesis, for which the
underlying principles are just beginning to be elucidated
(Bellion et al., 2005;
Kappeler et al., 2006;
Nasrallah et al., 2006), very
little is known about the cellular mechanisms that control the directional
movement of cortical interneurons in response to all these multiple guidance
cues. Our results suggest that dynamic regulation of leading process branching
is an essential mechanism for directional guidance in tangentially migrating
interneurons.
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MATERIALS AND METHODS |
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SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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;
López-Bendito et al.,
2004). The day of vaginal plug was considered to be embryonic day
(E) 0.5. Animals were maintained under Spanish and EU regulation.
Slice and explant culture experiments
Organotypic slice cultures of the embryonic mouse telencephalon were
prepared as previously described (Anderson
et al., 1997). In some experiments, vehicle solution
(H2O) or Y27632 (30 µm) was added to the medium 12 hours after
culture and replaced after 12 hours. Slices were then cultured for another
12/24 hours. For immunohistochemistry, slices were re-sectioned to 60 µm
and incubated with rabbit-anti GFP (1:2000, Invitrogen) overnight at 4°C
followed by 488 Alexa donkey anti-rabbit (1:500, Invitrogen) for 2 hours at
room temperature. Slices were mounted using Mowiol-Dabco with Bisbenzamide
(1:1000, Sigma).
Medial ganglionic eminence (MGE) explants were dissected out from E13.5
slices and confronted with COS cell aggregates (expressing dsRed
alone, or dsRed and Ig-Nrg1) in Matrigel matrices. Explants
were incubated for 12 hours at 37°C in Neurobasal (Invitrogen, San Diego,
CA) before the addition of vehicle or Y-27632 (30 µm). Vehicle and
inhibitor were replaced after 12 hours and explants incubated for a total of
48 hours. In other experiments, small pieces of the MGE from E13.5
Gfp transgenic mice were transplanted into wild-type host slices, as
described elsewhere (Marín et al.,
2003).
For acute treatment of individual neurons, micropipettes (tip diameter
1 µm) were placed above (10 µm) and at a distance of 20
µm from superficial dsRed-expressing neurons. Pressure pulses (0.1-0.4 bar;
duration, 20 ms) were applied at a frequency of 2 Hz for 1 hour. Pipette
solution contained Y27632 (3 mM) or the recombinant EGF domain of Nrg1
(NRG1-β1, Peprotech; 13 nM), and 0.4 mM Alexa Fluor 488 sodium salt
(Invitrogen) dissolved in PBS or H2O.
In vitro focal electroporation
pCAGGS-based Gfp and dsRed expression vectors were
pressure injected focally into the MGE of coronal slice cultures and focally
electroporated as described before (Flames
et al., 2004).
Time-lapse videomicroscopy
Slices were transferred to the stage of an upright Leica DMLFSA or inverted
Leica DMIRE2 microscope coupled to a confocal spectral scanning head (Leica
TCS SL) and viewed through 10-60x water immersion or 20x oil
objectives. Slices were continuously superfused with warmed (32°C)
artificial cerebrospinal fluid at a rate of 1 ml/minute or maintained in
supplemented neurobasal medium.
Quantification
Canvas (ACD Systems) and ImageJ (NIH,
http://rsb.info.nih.gov/ij/)
software were used for image analyses. For single pair-wise comparisons, a
two-tailed t-test was used. Chi-square analysis was used to compare
frequency distributions.
In co-culture experiments (Fig. 4), the migration angle was measured between the virtual vertical lines positioned at 0 or 90° (for quadrants 1 or 4, respectively) and the leading process closer to the COS aggregate.
For the analysis of the orientation of migrating cells at the pallial/subpallial boundary in slice cultures (Fig. 5), a virtual box (366 µm2x225 µm2) was defined at the place in which interneurons arrive to the cut in each slice. Cells within the box and in the adjacent 150 µm on both sides were classified into one of three groups depending on the orientation of their leading process: type 1 (leading process parallel to the cut), type 2 (process away from the cut) and type 3 (process towards the cut) cells. In cells displaying more than one leading process branch, the one with the swelling was selected. In few cases in which this was not evident, we consistently selected the widest and/or longest of the branches. To maximize the resolution of the cell morphology, cells were identified in 15-25 µm z-stacks.
For the analysis of the orientation of migrating cells in the cortex of slice cultures (Fig. 6), we identified Gad65-Gfp/BrdU double-positive cells in each slice and their main leading process was drawn using Canvas software. The main process was defined as that containing the organelle swelling in front of the nucleus; in a few cases in which this was not evident, we consistently selected the widest and/or longest of the branches. For each slice, we draw a grid of virtual radial lines (lines perpendicular to the ventricular zone and the pia) and orientated each cell in relation to the most adjacent `radial line'. Cells that deviated less than 25° from radial lines were considered as radially oriented; those that deviate more than 25° were designated as tangentially oriented (Fig. 6F). We systematically exclude from this analysis those cells located in the more lateral or medial regions of the cortex, so that the curvature of the slice in those regions would not interfere with our analysis.
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RESULTS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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-aminobutyric acid-containing (GABAergic) neurons express Gfp
(López-Bendito et al.,
2004), revealed that a branched leading process is a common
feature of many tangentially oriented neurons in different regions of the
brain and spinal cord (see Fig. S1 in the supplementary material)
(Ward et al., 2005). To study
the dynamic behavior of leading process branching in migrating interneurons,
we used confocal time-lapse videomicroscopy in organotypic slice cultures. In
this preparation, migrating interneurons display morphologies that closely
resemble those described in vivo (Fig.
1A,B) (Ang et al.,
2003). In a first series of experiments, we carried out focal
electroporation of a plasmid encoding for the red fluorescence protein dsRed
in the MGE of E13.5 telencephalic slices to label putative GABAergic
interneurons and performed time-lapse videomicroscopy after 12-36 hours in
culture (Fig. 1C,D). Using this
approach, we labeled a reduced number of relatively scattered interneurons per
slice, which allowed maximal resolution of the individual processes in each
migrating cell. Every tangentially migrating interneuron observed displayed
stereotyped dynamics (n>200 cells from at least 30 independent
experiments), including nuclear movements in register with constant remodeling
of the leading process. A representative case is presented in the sequence of
photographs shown in Fig. 1E.
At some point during their migratory cycle, all interneurons display a
branched leading process, with the soma and the nucleus located at a specific
distance behind the bifurcation (Fig.
1E) (t=0:00 h). Forward movement of the nucleus occurs in
a two-step sequence, as previously described
(Bellion et al., 2005;
Schaar and McConnell, 2005)
(see Fig. S2 in the supplementary material). First, a dilatation of the cell
soma located in front of the nucleus moves forward towards the bifurcation
(Fig. 1E) (t=0:10 h).
This movement is subsequently followed by the forward displacement of the
nucleus until it reaches the bifurcation
(Fig. 1E) (t=0:30 h).
After reaching the branching point, which is maintained stationary during
nucleokinesis, the nucleus continues moving forward along one of the branches
(Fig. 1E) (t=0:52 h).
Furthermore, when the nucleus enters one of the primary branches, the other
branch is already retracting and eventually becomes integrated in the trailing
process (Fig. 1E)
(t=0:52 h). Observation of migrating neurons for extended periods of time revealed that the sequence of steps described above represents a migratory cycle that is consistently repeated by tangentially migrating interneurons. A typical example is presented in the sequence of photographs shown in Fig. 1F, which illustrate the dynamic behavior of a tangentially migrating interneuron (see also Fig. 1F'; see Movie 1 in the supplementary material). The movement of this cell can be described by successive translocations of the nucleus along one of the branches of the leading process from one bifurcation point to the next one, in a sequence that is continuously repeated. Thus, with the exception of small and transitory branches (Fig. 1F, small arrows), the bifurcation point of the leading process consistently marks the future position of the nucleus at the end of each nucleokinesis (Fig. 1F, broken lines). In many cases, the non-selected branch retracts before the nucleus reaches the branching point (Fig. 1F) (t=6:45 h; n=47 out of 83 retracting branches, from 38 different cells). In the remaining cases, the branch that is not selected by the nucleus becomes the trailing process (Fig. 1F) (t=2:45 h; n=36 out of 83 retracting branches, from 38 different cells), and eventually disappears. Branch selection correlated with rapid changes in the morphology of the growth cones tipping the leading process branches: selected branches displayed elaborate growth cones, whereas the growth cone of non-selected branches showed a collapsed morphology prior to retraction (see Fig. S3 in the supplementary material). We also performed time-lapse videomicroscopy in acute E15.5 telencephalic slices obtained from Gad65-Gfp transgenic mice. Simultaneous analysis of multiple GFP-expressing cells in the cortex of Gad65-Gfp embryos revealed that interneurons tangentially migrating through the subventricular zone (SVZ), intermediate zone (IZ) or marginal zone (MZ) navigate by alternative selection of leading process branches, independently of their speed of migration (see Movie S2 in the supplementary material; n>200 cells from at least 20 slices). In conclusion, bipolar morphologies such as those observed in static images (Fig. 1A) represent a phase in the migratory cycle of tangentially migrating neurons, in which the leading process remodels continuously as they move.
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;
Polleux et al., 2002). Thus,
although the average angle between branches was only slightly larger in cells
migrating close to the cortical plate than in cells migrating through the LGE
or SVZ (51.74°±2.52°, n=102 cells)
(Fig. 2D'), we observed a
prominent increase in the frequency of cells that displayed relatively large
angles (Fig. 2D',
asterisks). There were two possible interpretations of these results. One
alternative is that the region of the cortical plate contains two distinct
populations of migrating interneurons, which branch at different angles.
Another possibility is that the same cells can make relatively small or large
branch angles depending on the environment. In agreement with this second
hypothesis, dynamic analysis of interneurons migrating around the cortical
plate revealed that rapid changes in direction are consistently preceded by
the formation of leading process branches at relatively large angles
(n=7 cells) (Fig.
2D''; see Movie 4 in the supplementary material).
Consistent with prior observations in LGE-derived SVZ neuroblasts
(Ward et al., 2005), our
previous results suggest that tangentially migrating interneurons change
direction by biased choices of leading process branches. In addition, the
differences observed in the net angle formed by leading process branches
between cells following quasi-linear trajectories and those rapidly changing
direction suggest that the amplitude of the angle at which new branches form
could be influenced by guidance cues present in the cortex. To test this
hypothesis, we performed experiments in which we forced interneurons migrating
in a steady path to rapidly change their trajectory. For this, we focally
electroporated the MGE of embryonic slices with dsRed and perfused
the vicinity of individual migrating cells with a glass micropipette
containing the cortical interneuron chemoattractant neuregulin 1 (Nrg1) (13
nM) (Flames et al., 2004). In
these experiments, we consistently placed the micropipette perpendicular to
the route followed by individual cells to stimulate a swift turn
(Fig. 3A-A''). Observation
of the migratory behavior of individual cells acutely attracted to a source of
Nrg1 revealed that direction change was always preceded by the generation of a
new leading process branch at a large angle (>60° in nine out of nine
cells) (Fig. 3B,B',C; see
Movie 5 in the supplementary material). This new leading process branch was
consistently oriented towards the source of the attractant, and was far more
likely to be maintained than those extending in other directions (nine out of
nine cells). This suggested that interneurons orient up intense
chemoattractant gradients by branching the leading process at relatively
larger angles than when they navigate in a constant direction, and by
consistently choosing the new, better aligned branch, in their subsequent
nuclear movement.
|
). When
applied to telencephalic slices, the ROCK1/2 inhibitor Y-27632 (30 µM) also
decreased the migration of cortical interneurons (n=19 slices) (see
Fig. S5 in the supplementary material). As expected
(Causeret et al., 2004),
decreased migration was in part due to a reduction in the frequency of
nucleokinesis in tangentially migrating neurons (n=6 cells) (see Fig.
S6 in the supplementary material). However, we also found that bath
application (n=35 cells) (see Fig. S5 in the supplementary material)
or direct pipette perfusion with Y27632 (n=5 cells) (see Fig. S7 and
Movie 6 in the supplementary material) decreased the frequency of leading
process branching in cortical interneurons.
To evaluate the chemotaxis behavior of MGE-derived interneurons when
leading process branching is perturbed, we performed explant co-culture
experiments with a source of Nrg1 (Flames
et al., 2004). In brief, we co-cultured E13.5 MGE explants with
aggregates of COS cells expressing the secretable isoform of Nrg1
(Ig-Nrg1) in matrigel three-dimensional matrices
(Fig. 4A). In control
experiments, cells derived from an E13.5 MGE explant confronted with COS cells
transfected with a mock plasmid migrated uniformly in all directions
(Fig. 4B). To quantify the
effect of Nrg1 on the trajectory of the neurons, we subdivided the circle
enclosing the MGE explant into eight sectors of equal size and measured the
maximum angle at which migrating cells deviate from the vertical (migration
angle, 
) (Fig. 4E). In
control experiments, this angle was roughly 45°, with a mean value of
35° (37.02±2.14°, n=167 cells from three
independent experiments) (Fig.
4B',E,F). By contrast, when MGE explants were co-cultured
along COS cells expressing Nrg1, the maximum migration angle observed within
sectors 1 and 4 was roughly 90°, with a mean value of 50°
(49.65±1.29°, n=520 cells from three independent
experiments) (Fig.
4C,C',E,F). These values reflect that many neurons derived
from the MGE were attracted towards a source of Nrg1
(Flames et al., 2004), and
therefore they reoriented their migratory path towards the COS cell aggregate.
As in slices, addition of Y27632 to the explant culture medium modified the
morphology of migrating neurons, decreasing the number of processes generated
by interneurons (n=317 cells from three independent experiments)
(Fig. 4G). In this scenario,
migrating interneurons failed to reorient their migration towards Nrg1. The
migration angle of MGE-derived neurons in response to Nrg1 in the presence of
Y27632 was similar to that of explants confronted with control COS cells
(38.10±1.41°, n=381 cells from three independent
experiments) (Fig.
4D,D',E,F), demonstrating that interneurons failed to
reorient when leading process branching is perturbed.
|
),
but they are forced to turn 90° laterally when they reach the incision
(Fig. 5A). Prior to the arrival
of interneurons to the incision (Fig.
5A,B), we added vehicle solution or Y27632 (30 µM) to the
culture medium to test whether leading process branching was required for this
rapid change of direction. After 12 additional hours in culture, we examined
the orientation of GFP-expressing cells close to the incision
(Fig. 5A). In control
experiments, most migrating cells where oriented parallel to the incision
(Type 1 cells) (Fig.
5C,C',E,F), suggesting they have turned 90° after
reaching the cut. In the presence Y27632, which decreases leading process
branching (see Fig. S7 in the supplementary material), the percentage of
migrating cells parallel to the incision was significantly reduced compared
with controls (Fig.
5D,D',E,F). Conversely, many more cells remained oriented
towards the incision in Y27632-treated slices than controls (Type 3 cells)
(Fig. 5D,D',E,F). These
experiments reinforced the view that leading process branching is required by
interneurons to perform considerable changes in their migratory direction.
|
;
Polleux et al., 2002)
(Fig. 6A). Although the
molecules involved in this process are currently unknown
(López-Bendito et al.,
2008), we hypothesized that leading process branching would also
be required for interneurons to perform this rapid change in direction (as in
Fig. 2D''; see also Movie
5 in the supplementary material). To test this idea, we prepared slices from
E15.5 Gad65-Gfp embryos that had received a BrdU pulse at E13.5 to
unequivocally identify a cohort of synchronically born interneurons. At E15.5,
interneurons have not yet begun to change their migration from tangential to
radial, and most cells display a tangential orientation (94.56±1.61 %,
n=74 cells from three slices of two independent experiments)
(Fig. 6B). After 2 DIV,
however, almost half of the entire population of interneurons has changed
their orientation to radial (41.99±5.37% radially oriented,
58.00±6.02 % tangentially oriented; n=231 cells from four
slices of two independent experiments)
(Fig. 6C,E-G). By contrast,
incubation of slices with Y27632 (30 µM) greatly reduced the transition of
migrating interneurons from tangential to radial orientation
(23.21±2.42% radially oriented, 76.79±2.42% tangentially
oriented, n=280 cells from four slices of two independent
experiments) (Fig. 6D-F,H).
Altogether, our experiments strongly suggest that leading process branching is
required for the chemotaxis of cortical interneurons. |
DISCUSSION |
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SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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). By contrast, the observation of both bifurcated and
non-bifurcated leading processes in tangentially migrating interneurons have
led to the suggestion that different types of cortical interneurons may use
different modes of migration (Nasrallah et
al., 2006; Polleux et al.,
2002). Our results demonstrate that the same cells adopt these two
different morphologies as part of their migratory cycle, suggesting that
leading process branching is part of the mechanism used by cortical
interneurons to migrate. Interestingly, many other tangentially migrating
neurons appear to branch their leading process as part of their migratory
cycle (López-Bendito et al.,
2006; Ward et al.,
2005) (this study), suggesting that this might be a general
feature for very distinct neuronal types. This, however, does not imply that
all neuronal populations undergoing tangential migration have branched leading
processes. For example, tangentially migrating precerebellar neurons display a
single leading process during their entire trajectory
(Bourrat and Sotelo, 1990).
The use of branches during tangential migration has been previously
interpreted as a mechanism employed by the cell to explore a wide territory,
in which guidance signals encountered by the tips of both branches, attractive
or repulsive, are likely to be different
(Ward et al., 2005). The
differential activation of guidance receptors at both branches could lead to
different signaling activities, which may then translate into distinct
tendencies towards growth or collapse. Once the misbalance between signals at
both branches reaches a crucial level, then one of the branches retracts and
the other stabilizes. These observations suggest that the dynamic behavior of
the two leading processes is highly interdependent, functioning in a
continuous competing mode: a one-win/one-lose dichotomy. In that sense, the
behavior of cortical interneurons appears to resemble more closely that of
some unicellular organisms in which chemotaxis involves the generation of new
protrusions by splitting the leading edge of the cell
(Andrew and Insall, 2007).
Whether similar mechanisms coordinate the generation of new pseudopods in
Dictyostelium and leading process branches in cortical interneurons
remains to be elucidated.
Leading process branching mediates directional guidance
For axons, directional growth in response to chemotactic cues is thought to
involve a compass-like behavior in which axons are continuously instructed to
the correct direction by differential actin polymerization across the growth
cone (Wen and Zheng, 2006). In
the case of tangentially migrating neurons, the dynamic behavior of the
leading process, which continuously branch as part of the migratory cycle,
suggests that these cells do not achieve directional migration through a
mechanism that involves leading process steering. In these cells, growth cone
dynamics seem to be relevant only for the initial orientation of the branch.
After that, they appear to serve exclusively for the elongation or retraction
of the branches, the orientation of which remains stable during their entire
lifetime. Consequently, directional movement is mediated by biased choices of
nuclear movements into one of the leading process branches.
During quasi-linear migration, the nucleus alternates branches to maintain
a defined course. Remarkably, the probability of selecting each of the two
alternative branches is almost 50% during quasi-linear migration, which
suggest that interneurons are set to follow a rather constant course when
migrating in relatively shallow chemotactic gradients. By contrast, our
observations suggest that interneurons achieve rapid changes of direction by
modifying their basic behavior of leading process branching and selection.
Under the influence of intense chemoattractant gradients, interneurons retract
systematically those branches that are not oriented towards the source of the
chemoattractant, branch at larger angles than they normally do when migrating
in quasi-linear trajectories, and preferentially select the new branches,
which are better aligned with the source of the chemoattractant. The
importance of leading process branching in directional guidance is illustrated
by our pharmacological manipulations, which suggest that a perturbation of the
frequency at which interneurons branch their leading process alters their
ability to react to guidance cues (e.g. Nrg1). A caveat of these experiments,
however, is that blocking ROCK could not just prevent branching, but also
directly interfere with Nrg1 signaling. We believe this is unlikely because
inhibition of Rho-ROCK signaling appears to enhance rather than inhibit
chemoattractive guidance in spinal commissural axons
(Moore et al., 2008).
Moreover, ROCK inhibition does not block Nrg1-mediated cell adhesion in B
lymphoblasts (Kanakry et al.,
2007), suggesting that Nrg1 signaling does not involve ROCK
function. In any case, inhibition of leading process branching in slice
cultures also makes rapid directional changes more difficult for interneurons
under other circumstances. For example, inhibition of branch formation reduce
the ability of interneurons to turn under mechanical constrains or during the
process of cortical plate invasion. These experiments reinforce the view that
the dynamic behavior of leading process branching is required for the
chemotaxis of tangentially migrating interneurons.
In conclusion, our results suggest that directional migration can be achieved not only through growth cone steering, as it happens in neurons with a bipolar shape, but also by biased choices of leading process branches in those neurons that have a leading process with a more elaborate morphology.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/136/1/41/DC1
|
Footnotes |
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* These authors contributed equally to this work 
These authors contributed equally to this work
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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2 test,
***P<0.001). (B'',D'')
Superimposed images of movie frames recreate the path followed by migrating
neurons in the LGE (B'') and CP (D''). Green dots indicate the
position of the nucleus in each nucleokinesis. Diagrams depict directional
changes in these cells. New branches are shown in green, and the chosen branch
is marked with a red arrowhead. Numbers indicate the angle formed by the
branches. ac, anterior commissure; H, hippocampus; MZ, marginal zone; NCx,
neocortex; PCx, piriform cortex; Str, striatum. Scale bars: 500 µm in A; 25
µm in B-D; 20 µm in B'',D''.
