Department of Neuroscience, Unit of Developmental Neuroscience, Biomedical Center, Uppsala Univeristy, S-751 23, Uppsala, Sweden
* Author for correspondence (e-mail: finn.hallbook{at}neuro.uu.se)
Accepted 2 December 2003
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SUMMARY |
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Key words: Biolistic gene transfer, Chicken, Cytochalasin D, GABA, Lamination, Lim1, Migration, Prox1, Retina
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Introduction |
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Currently there are two modes of migration identified in the developing
avian retina (Prada, 1983). Early in chick retinal development, before
Hamburger and Hamilton stage (st) 22-25 (equivalent to embryonic day 4, E4),
cycling progenitor cells are undergoing radial migration manifested by a
nuclear translocation across the neuroepithelium, while the cellular end-feet
remain connected to the ventricular zone. After cell division at the
ventricular side, post-mitotic cells that are committed to a certain precursor
lineage, are thought to detach their end-feet and migrate freely to a specific
lamina where they will start the maturation process. The free migration is
predominant in chicken retina from st24 to st33. Furthermore, after the
initial period (from st25 and beyond) with uniform mitotic activity over the
entire surface of the retina, the development spreads in a centrifugal
gradient both in a dorsal to ventral and nasal to temporal direction. Thus,
the central parts of the retina are always more mature relative the peripheral
parts (Prada et al., 1991).
The first cells to withdraw from the cell cycle and differentiate are the
retinal ganglion cells, followed by the overlapping birth of amacrine cells,
horizontal cells (HC), cone photoreceptors and Müller glia cells. The
last cells to withdraw from the cell cycle are the bipolar cells and rod
photoreceptors. The majority of the retinal ganglion cells, amacrine cells and
HC withdraw from the cell cycle around st19-22 (E3) but the cellular birth of
these classes are not fully completed until st25-28
(Altshuler et al., 1991
;
Kahn, 1974
;
La Vail et al., 1991
;
Young, 1985
).
This work was initiated by an observation in our previous work
(Karlsson et al., 2001), in
which we found that cells thought to be HCs and that expressed nerve growth
factor and its receptor TrkA, were translocated from the vitreal to the
ventricular side of the retina. In the present study we have investigated how
prospective HC, defined here as cells positive for the homeobox-containing
transcription factors Lim1 (Lhx1) and Prox1
(Adler and Belecky-Adams, 1999
;
Dyer et al., 2003
;
Liu et al., 2000
;
Tomarev et al., 1996
), migrate
during retinal development. The current view holds that HCs migrate only a
short distance from their place of birth to their final position
(Adler, 2000
;
Mey and Thanos, 2000
; Prada,
1983; Stone, 1988
). However,
based on the distinct spatiotemporal changes of the Lim1/Prox1 labelling
patterns, we propose that newborn Lim1-positive (+) HC precursors undergo a
previously undocumented pattern of free migration before attaining their final
position in the external part of the inner nuclear layer. The results do not
exclude that other cells may take a similar migration route. In short, the
observed migration starts at st24-26, when newborn horizontal cells first
undergo vitreal-directed migration from their site of birth to the lining of
the prospective ganglion cell layer where they reside from st27-30, before
undergoing a phase of ventricle-directed migration to reach their definite
position in the external part of the inner nuclear layer by st33-34. In order
to further collect evidence for the proposed migration we inhibited cell
motility using a cytoskeleton inhibitor and using biolistic gene transfer
together with timelapse microscopy we could document ventricle-directed
migration.
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Materials and methods |
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Time-lapse and particle-mediated gene transfer
Particle-mediated gene transfer ('biolistics') using a Helios Gene gun
(BioRad) was used to transfect retinal cells with a green fluorescent protein
(GFP) expression vector (Lo et al.,
1994; Yang et al.,
1990
). One micron gold particles (BioRad) were coated with the
pEGFP-C3 plasmid. Cartridges for gene gun transfection were prepared according
to the manufacturer's instructions. Retinas for transfection were dissected in
temperature controlled Neurobasal medium (no. 21103, Invitrogen, supplemented
with 0.05 M Hepes and 1% penicillin/streptomycin) and flat-mounted with the
ganglion cell layer facing up on a nitrocellulose filter (13006-50-N;
Sartorius). After flat-mounting, the remaining medium was carefully removed
not to obstruct the gold particles. The tissue was then immediately bombarded
at 160 psi using the Gene gun. The He gas pressure used to accelerate the gold
particles was calibrated so that the particles would penetrate up to 25 µm
into the retina. Thus, only cells with their soma located not more than a few
cell diameters into the retina were hit by the particles. Retinas on filters
were then incubated in medium at 37°C in a humidified atmosphere
containing 5% CO2 for various times. After bombardment, the retinas
were incubated for 4-6 hours before being cut into 0.20 mm thin slices using a
vibratome and several slices with retina were positioned on a glass coverslip
in the bottom of a Syke's Moore chamber (no. 1943-11111, Bellco Glass Inc.,
USA). The slices (flipped 90 degrees relative to the cut) were fixed using
Vaseline so that a cross section of the retina was visible. The chamber was
then filled with medium, sealed and coupled to a temperature controller
(FCS-100, Shinko Technos, Japan) keeping a constant temperature at 37°C.
Regions with many successfully transfected cells were selected and the
time-lapse specimens were studied using a Zeiss Axioplan2 microscope with
Axiovision software (3.0.6.1, Carl Zeiss Vision GmbH). For combined GFP
transfection and immunohistochemistry, retinas were transfected as above and
kept flat-mounted under the same conditions for the desired time (ranging from
15 minutes to 24 hours). The flat-mounted retinas were subsequently fixed with
4% PFA at 4°C, washed in PBS, cryoprotected in 30% sucrose, embedded in
OCT (Sakura, The Netherlands), frozen, cut in 10 µm thick sections using a
cryostat and collected on SuperFrost Plus glasses (Menzel-Gläser,
Germany). Immunohistochemistry was carried out as described below.
BrdU incorporation
For 5-bromo-2'-deoxyuridine (BrdU) incorporation, 40 µg of BrdU
(Sigma, St Louis, MO) was injected into the yolk of embryo cultures 12-16
hours before the desired stage of analysis. The embryo was kept in culture
until analysis and the eyes were prepared for immunohistochemistry as
described below. Only the central part of the retina was used to count cells
that had incorporated BrdU, in order to adhere to a specific embryonic
stage.
Migration inhibition assay
To inhibit migration, 0.2-2 µl of 2 mM actin polymerisation inhibitor
cytochalasin D (Bruijns and Bult,
2001) (Sigma-Aldrich) was injected into the vitreous body of st29
embryos using pulled capillaries and a SP100i digital infusion syringe pump
(World Precision Instruments, Sarasota, FL). The cytochalasin D was dissolved
in 62% DMSO and was supplemented with Fast Green (C8686, Kodak) for
visualisation purposes. Injections were carried out four times at 12-hour
intervals and the embryos were sacrificed upon reaching st33. We also carried
out injections with the microtubule inhibitor Colcemid (Molecular Probes,
Leiden, The Netherlands) at a concentration of 100 µM (containing 1% DMSO)
with 24 hours intervals. Apart from the frequency of the injections, the
procedure was otherwise similar to that for cytochalsin. Controls received
vehicle solution also containing Fast Green using similar regimens.
Immunohistochemistry
After dissection, whole eyes were fixed in 4% PFA at 4°C, washed with
PBS for 10-15 minutes, cryoprotected in 30% sucrose at 4°C, embedded in
OCT freezing medium, frozen and cut in a cryostat. Horizontal sections, 10
µm thick (12 µm for st44 and st45 eyes) were taken from the centre of
the specimen at the level of the lens and collected on SuperFrost Plus
glasses. For immunohistochemistry, the sections were rehydrated in PBS for 15
minutes and then blocked in PBS containing 1% foetal calf serum and 0.1%
Triton X-100 for 30 minutes. Primary and secondary antibodies were diluted in
this solution. Primary antibodies were allowed to react with the samples for 2
hours at room temperature or overnight at 4°C, and secondary antibodies
for 2 hours at room temperature. Primary antibodies used in this study were
directed towards Lim1/2 (1:5-50, 4F2, Developmental Studies Hybridoma Bank
DSHB), Ng-CAM [1:2000, (de la Rosa et al.,
1990)], Prox1 (1:4000, gift from Dr M. Nakafuku), GABA (1:1000,
A2052; 1:500, A0310, Sigma), Pax6 (1:200, PAX6, DSHB), Lim3 (1:200, 67.4E12,
DSHB), Ap2
(1:200, 3B5, DSHB), Islet1 (1:200, 40.2D6, DSHB), Chx10
(1:4000, gift from Dr J. Ericson), calretinin (1:1000, 1741-1007, Anawa,
Zürich), Brn3a (1:100, MAB1585, Chemicon), Brn3b (1:200, sc-6026, Santa
Cruz) and BrdU (1:50, M20105S, Biosite). Secondary antibodies were obtained
from Vector Laboratories (Burlingame, CA) and Molecular Probes (Leiden, The
Netherlands) and diluted 1:200. Sections were studied using a Zeiss Axioplan2
microscope and Axiovision. Graphical enhancing and preparation for publication
were performed using Axiovision and Photoshop (v6.0.1, Adobe).
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Results |
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Time-lapse microscopy at st31 reveals ventricle-directed migration
We also used a direct approach to study if cells undergo ventricle-directed
migration in the retina, which would be in agreement with the hypothesised HC
migration. Dissected and flat-mounted st31 retinas were bombarded on the
vitreal side (ganglion cell layer-face) by 1 µm gold particles coated with
a GFP expression vector using a Gene gun. The acceleration of the gold
particles was calibrated so that the particles would penetrate up to 20-25
µm into the retina. Thus, only cells with their soma located not more than
a few cell diameters into the retina were hit
(Fig. 3F). A fraction of those
cells were transfected and later expressed the transgene. GFP expression could
be detected after 30-60 minutes. For fluorescence time-lapse microscopy, 200
µm thick slices of the biolistically transfected retinas were cut and
mounted in a microscope-fitted tissue chamber. The results showed that
GFP-expressing cells could be found in the internal regions of the
neuroepithelium (Fig. 3) and
the time-lapse analysis showed that cells migrated away from the vitreal side
of the neuroepithelium (Fig.
3A-C).
|
The Lim1-expressing cells are both GABA- and calretinin-positive horizontal cells
We wanted to confirm that Lim1 and Prox1 cells were indeed HCs and
therefore co-labelled them with antibodies directed towards GABA and
calretinin, two well-known markers for HCs
(da Costa Calaza et al., 2000;
Ellis et al., 1991
;
Yazulla, 1986
). At st44, we
could find a perfect overlap of Lim1 and GABA at the level of the HCs
(Fig. 4A-D). Co-labelling of
GABA and Prox1 in the HC layer was also found at this stage (results not
shown). At st45 we found a perfect overlap between Lim1 and calretinin
(Fig. 4E-H). These labelled
cells have the typical shape of HCs as visualised by both GABA and calretinin
immunoreactivity (Fig. 4A,E). Both GABA and calretinin were also found in those parts of the inner nuclear
layer and ganglion cell layer where one can expect to find these markers
(results not shown).
|
Unlike Pax6 and Ap2, labelling for the transcription factor Lim3
produces a strong signal on the ventricular side of the developing retina
(Fig. 5G,J) and double
labelling with Lim3 and Prox1 at st35 shows no overlap between these
transcription factors. Instead, the factors are expressed in distinct laminas
(Fig. 5G-I). Among post-mitotic
retinal cells, the transcription factor Chx10 is exclusively expressed in
bipolar cells (Chen and Cepko,
2000
; Dyer, 2003
)
and labelling for Chx10 reveals a band of cells just below the HC layer; the
inner external INL (Fig. 5J-L).
Chx10 overlaps with Lim3 (Fig.
5J-L) but not with Lim1 (Fig.
5N-O) or Prox1 (Fig.
5B,E,H,K), except for a slight overlap between Prox1 and weak
Chx10 expression in the central INL (compare
Fig. 5B,E,H with K,N). These
patterns distinguish the HCs from their nearest surrounding cells and are in
clear agreement with the proposed HC migration into their mature positions
next to the outer plexiform layer.
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Discussion |
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Although the bi-directional migration of HCs has not explicitly been
demonstrated previously, ventricle-directed migration of newborn retinal
neurons finds indirect support in both previous studies and more recent ones.
Based on serial sections Hinds and Hinds suggested as long ago as 1978 that
cells in the mouse retina may take a route of migration that includes passing
the vitreal side of the neuroepithelium before ending up in the inner nuclear
layer (Hinds, 1979;
Hinds and Hinds, 1978
). It was
suggested that this alternative route could explain the presence of displaced
amacrine cells in the ganglion cell layer. However, this suggestion was
rebutted by others (Prada et al.,
1987
; Prada, 1983). Although Prada and co-workers were opposed to
the idea of ventricle-directed migration, they indicated the presence of
HC-like cells in the vitreal side of the retina
(Prada et al., 1984
). Despite
their migration dispute, both Hinds and Prada generally agreed that newborn HC
only migrated from their place of birth directly to their final position close
to the outer plexiform layer (Fig.
6A). Other researchers, however, disagreed with this view, resting
their case on observations of "common neuroblasts of horizontal and
amacrine cells", which at E7 (st30-31) were located close to the
ganglion cell layer before some of these neuroblasts underwent
ventricular-directed migration and ending up close to the outer plexiform
layer by E8.5-9 (st35) (Gallego,
1986
; Tarrés and
Gallego, 1984
). Moreover, in a report from 1987 Prada describes
two populations of amacrine cell precursors based on their shape and migratory
behaviour; the `smooth' and `multipodial' amacrine cell
(Prada et al., 1987
). The
`smooth' amacrine cells were radially disposed on the vitreal side at E5
(st26-28) but "diminished drastically" by E7 (st30-31) at the same
time as free neuroblasts were found close to the ventricular side, indicating
them to be HCs. We suggest that the `smooth' amacrine cells, in fact, were the
migrating HCs reported on herein.
More recent reports indicate the presence of retinal cells with immature HC
markers located vitreally in the neuroepithelium of birds and mammals. Liu et
al. found that in the E16.5-E18.5 mouse retina some Lim1+ cells could be found
outside their proper lamina (Liu et al.,
2000). In two reports on GABA expression during development in the
chick and human embryo, `ectopic' expression was found at time points that
corresponds to our current observations
(Hokoc et al., 1990
;
Nag and Wadhwa, 1997
).
Furthermore, a previous observation in our laboratory, which prompted us to
undertake this study, showed how the pattern for nerve growth factor
expression changed from being located vitreally at E5.5-E6 (st27-29) to be
expressed in the external inner nuclear layer later
(Karlsson et al., 2001
). The
cells were identified as HCs.
The detailed temporal analysis of the genes expressed by HCs (Fig. 1) gives strong support to the ventricle-directed migration. This is further strengthened by the fact that the translocation of Lim1 cells is inhibited by the cytochalasin D injection (Fig. 2F-H) in a dose-dependent manner showing that the changing patterns are not the result of transient expression in various layers of the retina. Another piece of evidence is the time-lapse recording of cells that move in the direction of the ventricle towards the prospective lamina of differentiated HCs (Fig. 3A-C). Similar cells can be identified as Lim1+ or Prox1+ cells (Fig. 3D-E). The time-lapse recording is a powerful technique in combination with particle-mediated gene transfer. The conditions for the preparation of biolistic particles and the bombardment were carefully controlled but there was a notable variation in the distribution of particles as well as transfection rate over the surface of the retina. The variation was partly batch related but was also seen between separate bombardments and this was most probably a result from the actual construction of the Gene gun. This variation made quantification difficult and is therefore not presented here.
The identification of Lim1+ cells as HCs was verified using GABA and
calretinin and the conspicuous morphology of mature HCs next to the outer
nuclear layer (Fig. 4A-H). On a
related topic, recent work by Nadarajah et al. showed that certain GABAergic
cortical interneurons display a ventricle-directed migration before attaining
their mature positions in the cortex
(Nadarajah et al., 2002) and
these observations could suggest that these cells may have additional features
in common.
Within the INL, and in the retina in general, the early born cells are in
the inner part and the late born cells in the outer part, with the clear
exception for HCs. The bi-directional migration of HCs, as shown in this work,
gives an explanation to this order and organisation. The order is further
supported by patterns of complementary expression of the homeobox
transcription factors in layers and sub layers of the retina
(Fig. 5). HCs express
transcription factors that are also expressed by cells in the early formed
inner retinal layers. In addition to the HC-specific Lim1 expression, Pax6 and
Ap2 are expressed by HCs. Pax6 is also expressed by cells in the
ganglion cell layer and internal INL and Ap2
is expressed by amacrine
cells in the internal INL (Fig.
5A-F). In contrast, and complementary to this pattern, Lim3 and
Chx10 (Fig. 5J-O) are expressed
by cells in the external INL with the clear exception of HCs. This exception
can be explained by the migration of HCs into this region.
Pax6, Lim3 and Chx10 are known to confer tissue-specific gene expression
and their own expression has been shown to be regulated by morphogens such as
Sonic hedgehog (Ericson et al.,
1997). Retinal differentiation as well as lamination is thought to
be modulated by external signals polarised from either the pigment epithelium
(Raymond and Jackson, 1995
) or
from the retinal ganglion cells (Wang et
al., 2002
). HCs will be exposed `en route' during migration to
signals present in the inner part of the retina. These signals can provide the
HCs with instructions necessary for their proper maturation. Furthermore, HCs
may `escape' from signals present in the outer parts of the retina during a
critical period. This implies that the fate and maturation of HC neurons are
not necessarily specified by their final position in relation to the polarised
signals in the retina as proposed previously
(Adler, 2000
;
Adler and Belecky-Adams,
1999
).
HCs are born early but establish synaptic contacts with bipolars and photoreceptors that are born late, and the function of the HCs is to modulate the visual information from photoreceptors to bipolars. This is reflected in the functional architecture of the retina where HCs are organised laterally. The proposed migration and the actual detour to the ganglion cell layer that leads to a delay of several days for the differentiating HCs, may constitute a mechanism by which the temporal sequence is achieved for the appropriate functional connections to be established within the outer plexiform layer.
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ACKNOWLEDGMENTS |
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