1 Department of Anatomy and Neurobiology, Washington University School of
Medicine, 660 South Euclid Avenue, Box 8108, St Louis, MO 63110, USA
2 Departments of Surgery, Oncology and Cell Biology, Johns Hopkins Medical
Institutions, Baltimore, MD 21287, USA
* Author for correspondence (e-mail: wongr{at}pcg.wustl.edu)
Accepted 5 September 2005
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SUMMARY |
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Key words: Amacrine, Stratification, Retina, Interneuron, IPL
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Introduction |
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The retina offers an attractive model to investigate how synaptic
specificity is achieved by interneurons. The stereotypic organization of this
structure is such that connectivity between cells is confined to two distinct
synaptic laminae, the outer and inner plexiform layers (OPL, IPL). Within the
IPL, connections between specific pre- and post-synaptic partners are
organized within two distinct sublaminae, each of which contains multiple
strata (Mumm et al., 2005;
Nelson et al., 1978
;
Pang et al., 2002
). By
monitoring how interneurons confine their arbors to specific sublaminae in
vivo, insights into the mechanisms that determine synaptic specificity can be
gained. Zebrafish, which are relatively transparent during development, are
well suited for such studies (Jontes et
al., 2000
; Kay et al.,
2004
; Mumm et al.,
2005
). Here, taking advantage of genetic constructs that
specifically label retinal amacrine cells in transgenic zebrafish, we
investigate how these interneurons organize their arbors within sublaminae to
target their synaptic partners in vivo.
Like many CNS interneurons, amacrine cells are inhibitory. Amacrine cells
modulate the vertical flow of visual information from photoreceptors via
bipolar cells to ganglion cells. They contact bipolar cell axons and ganglion
cell dendrites in the IPL. The IPL is further sublaminated to segregate
circuits that respond differentially to the onset of light. The processes of
cells that hyperpolarize with increased light intensity are confined to the
outer half (OFF sublamina) of the IPL, whereas processes of cells that
depolarize are confined to the inner half (ON sublamina)
(Famiglietti et al., 1977;
Famiglietti and Kolb, 1976
;
Stell et al., 1977
).
Birthdating studies in diverse vertebrates suggest that ganglion cells are
the first generated cell type (Hu and
Easter, 1999; Prada et al.,
1991
; Rapaport et al.,
1996
; Rapaport et al.,
2004
). Of the neurons that contribute their processes to the IPL,
the generation of ganglion cells is followed by the generation of amacrine
cells and bipolar cells in overlapping sequence
(Prada et al., 1991
;
Rapaport et al., 1996
;
Rapaport et al., 2004
). Our
own previous observations (Kay et al.,
2004
) and those of others
(Gunhan-Agar et al., 2000
;
Williams et al., 2001
) suggest
that in the absence of ganglion cells, amacrine cell arbors stratify within ON
and OFF sublaminae. Thus, despite their early generation, ganglion cells
appear to be dispensable for amacrine cell stratification. With no absolute
requirement for their major synaptic partners, how do amacrine cells achieve
their stratification pattern? This question has remained elusive, as available
immunocytochemical markers only label differentiated amacrine cells after they
are stratified (Bansal et al.,
2000
; Gunhan et al.,
2002
; Reese et al.,
2001
; Stacy and Wong,
2003
). It has therefore not been possible to determine whether
amacrine cell neurites remodel within the IPL before occupying a sublamina, or
whether they specifically target a sublamina, responding to cues already
present in the nascent IPL.
Here, we use two different genetic constructs to drive the expression of fluorescent proteins in amacrine cells in transgenic zebrafish. By using pancreas transcription factor 1a (ptf1a) regulatory elements to drive expression of green fluorescent protein (GFP), we were able to follow the entire population of amacrine cells during development and monitor how amacrine neurites contribute to the formation of the IPL.
To determine how individual amacrine cells stratify within the IPL, we used pax6 enhancer elements to drive the expression of fluorescent proteins in small subsets of amacrine cells. Because we followed individual cells from the time their neurites first elaborate until they stratify, we were able to gain insight into the developmental rules that govern amacrine cell stratification. Our observations provide the first view of how individual amacrine interneurons organize their processes to target specific synaptic partners within the sublaminae of the IPL. They also suggest that the strategies used by interneurons and projection neurons to achieve synaptic specificity could be diverse.
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Materials and methods |
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Labeling individual amacrine cells in ptf1a::GFP retinae
Two plasmids were injected into one-cell-stage fertilized eggs from crosses
of ptf1a::GFP fish. -tubulin::Gal4VP16 (pBtub-GVP)
(Koster and Fraser, 2001
) was
co-injected with UAS::M-mCherry. The latter plasmid was made by cloning the
14xUASE1b promoter (Koster
and Fraser, 2001
) upstream of a plasmid containing monomeric
Cherry (mCherry) (Shaner et al.,
2004
) fused to the first 20 amino acids of zebrafish Gap43, a
sequence containing palmitoylation sites
(Kay et al., 2004
). This
results in membrane targeting of the fluorescent protein (M-mCherry).
Generation of pax6DF4::M-CFP and M-YFP transgenic lines
Seven cyan fluorescent protein (CFP) and four yellow fluorescent protein
(YFP) transgenic lines of zebrafish (see Table S1 in the supplementary
material) were generated by modifying a plasmid previously used to drive
stable expression of membrane-targeted GFP in subpopulations of amacrine cells
(Kay et al., 2004). Briefly,
CFP or YFP was fused to a membrane-targeting sequence of zebrafish Gap43.
Expression of the fusion protein was regulated by an EF1
promoter and a hexamer of the DF4 pax6 enhancer element. Most of the
transgenic lines were generated in a wild-type background. However, three out
of the four YFP founders are carriers for roy orbison (roy),
a pigmentation mutant in which iridophores are reduced
(Ren et al., 2002
). The
development and histology of the retina in roy fish appear
indistinguishable from wild-type zebrafish
(Ren et al., 2002
).
Immunohistochemistry
Larval fish were fixed as described by Kay et al.
(Kay et al., 2004).
Cryosections (20 µm) were incubated in 5% normal donkey serum for 1 hour,
followed by an overnight incubation in mouse anti-5E11 (1:50, a gift from Dr
J. M. Fadool) or mouse anti-zn5 (1:500, Zebrafish International Resource
Center) diluted in 0.1 M PBS containing 0.5% Triton X-100. Following washes in
PBS and incubation in Alexa Fluor 568 goat anti-mouse (Molecular Probes;
1:1000 in 0.1 M PBS) for 1 hour, sections were cover-slipped in Vectashield
(Vector Laboratories). Alexa Fluor 633 Phalloidin (1:50; Molecular Probes) was
sometimes included with the primary antibody.
Live imaging
Embryos were prepared for in vivo imaging as described by Kay et al.
(Kay et al., 2004). A detailed
protocol is also available (Lohmann et
al., 2005
). Confocal image stacks were acquired on an Olympus
FV500 or a BioRad 1024M with water objectives, including a 60x (NA 1.1,
Olympus), a 100x (NA 1.0, Olympus) and a 4x air objective (NA
0.28, Olympus). A series of optical planes encompassing the entire neuritic
arbor of the cell being monitored was obtained at each time point. To follow
the motility of processes, images were obtained every 5 to 10 minutes for a
period of 30 minutes. For these experiments, the confocal aperture was fully
open to permit the use of minimal laser power and to reduce phototoxicity. To
monitor the lifetimes of amacrine cell processes, images were obtained every
minute, for 30 minutes.
Counter-staining transgenic embryos with BODIPY Texas Red
To define the retinal location of amacrine cells and to delineate the
boundaries of the IPL, embryos were counterstained with CellTrace BODIPY Texas
Red methyl ester (Molecular Probes), a vital dye that labels cell membranes
(Cooper et al., 2005). Embryos
were incubated for 1 hour in 200 µM BODIPY Texas Red in 0.3x
Danieau's solution containing 1-phenyl-2-thiourea (PTU). Following several
washes in 0.3x Danieau's solution, embryos were prepared for live
imaging.
Image analysis
Image analysis including orthogonal rotations and 3D reconstructions were
carried out using Metamorph (Universal Imaging) or Amira (TGS Template
Graphics software). They were further processed in Adobe Photoshop CS.
To assess directionality of neurite elaboration by immature amacrine cells, we imaged cells at 15-30 minute intervals over 2-3 hours. Three-dimensional reconstructions of the cells were analyzed at each time point. Two lines, at 90° angles to each other, intersecting the soma at its mid-point, served to partition the surrounding area into three regions: towards the outer limiting membrane (OLM), the ganglion cell layer (GCL) and sideways (S). We scored neurite tips as being oriented toward the OLM, GCL or sideways according to their localization within one of these areas.
To measure changes in neurite length, the distance between the tip of a process and its branch point or its point of origin on the cell body was measured using the xyz function of Metamorph. This measurement function takes into account the xy pixel size and the z-distance between optical planes.
Time-lapse images of isolated amacrine cells in the context of the
developing IPL were acquired approximately every 2 hours starting at day 3,
around 54 hours post-fertilization (hpf), and continued until day 4.
Synaptogenesis between amacrine and ganglion cells in the IPL commences at
around 60 hpf (Schmitt and Dowling,
1999). By the third day postfertilization (dpf), all cell and
plexiform layers are present. The first electroretinographic responses and
optokinetic reflexes are recorded around 4 dpf
(Easter and Nicola, 1996
;
Schmitt and Dowling, 1999
).
The densely labeled CFP+ plexus between the inner nuclear layer
(INL) and ganglion cell layer (GCL) in
[TG(pax6-DF4::M-CFP)Q01] provided the boundaries
of the IPL. At later time points, the demarcation between this plexus and
cells in the INL and GCL is definitive. Early in development, however, cells
(likely displaced amacrine cells) are found embedded within the plexus, giving
it a discontinuous appearance. At these stages the outer-most and inner-most
regions, where a continuous plexus was apparent, were defined as the IPL
boundaries.
To examine the distribution of processes of isolated amacrine cells (GFP+ or YFP+) in relation to the depth of the IPL (CFP+), we selected three image planes that excluded the cell body and rotated them orthogonally using Metamorph. At the orthogonal plane, a threshold was applied to the images. The IPL was divided into two equal halves, an outer (INL side, `OFF') and an inner (GCL side, `ON') sublamina. GFP or YFP pixel intensity within each sublamina was measured and averaged for the three image planes.
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Results |
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To examine how amacrine cells become displaced to the GCL and how the
GFP+ plexus emerges during development, we imaged the retinae of
ptf1a::GFP transgenic fish in vivo and counterstained the embryos
with BODIPY Texas Red to visualize the general structure of the retina
(Cooper et al., 2005). At early
time points, many GFP+ cells were detected two to three cell bodies
away from the ILM, overlying the GFP somata of ganglion
cells (Fig. 1B,C, see Fig. S1
in the supplementary material). Two morphologically distinct GFP+
somata could be distinguished. The vast majority of cells had elongated
somata, whereas a smaller number of vitreally located cells had rounded or
flattened somata (Fig. 1B,C).
Time-lapse imaging of individual, vitreally located amacrine cells clearly
revealed the orientation of their neurites towards the GFP+
amacrine cells in the INL from very early time points
(Fig. 1B, see Fig. S2 in the
supplementary material). Starting around 42 hpf, a GFP+ plexus
emerged between the two amacrine cell populations and, with time, the
vitreally located cells became displaced towards the GCL
(Fig. 1C). Although higher
resolution confocal imaging revealed some GFP+ neurites extending
towards the GCL (see Movie 1 in the supplementary material), the overwhelming
majority of GFP+ neurites was confined to the neuropil between the
two populations of amacrine cells. Thus, amacrine cells located in the INL and
displaced amacrine cells orient their neurites towards each other from the
outset. With time, the GFP+ amacrine neurite plexus transforms from
an apparently diffuse plexus at 51 hpf
(Fig. 1C) to a laminated plexus
by 76 hpf (Fig. 1A). How the
neuritic arbors of individual amacrine cells transform during this time could
not be gauged in ptf1a::GFP transgenic fish because of the high
density of labeling. We therefore sought alternative means to label individual
amacrine cells.
Amacrine cell-specific transgenic lines expressing different color fluorescent proteins
We previously used the pax6 enhancer element (pax6-DF4)
to generate stable transgenic lines (lines 220, 244 and 243) expressing
membrane-targeted GFP in subpopulations of amacrine cells
(Kay et al., 2004). The
neurites of the GFP-labeled amacrine cells ramify in two prominent sublaminae
within the IPL. Co-labeling of these GFP+ sublaminae with
immunoreactivity for choline acetyltransferase, suggested they correspond to
OFF and ON sublaminae (Kay et al.,
2004
; Yazulla and Studholme,
2001
). Variable levels of expression were seen between these lines
most likely caused by integration site effects, such that a high density of
GFP expression in some lines (line 220) made it difficult to distinguish
between the neuritic arbors of individual cells, whereas in other lines (lines
244 and 243) fewer amacrine cells were labeled
(Kay et al., 2004
).
To follow the behavior of individual amacrine cells, we took advantage of the variegated patterns of expression of the pax6-DF4 construct to generate stable transgenic lines expressing membrane-targeted CFP or YFP. Seven CFP [TG(pax6-DF4::M-CFP)] and four YFP [TG(pax6-DF4::M-YFP)] transgenic lines were generated (see Table S1 in the supplementary material). For simplicity, these lines are referred to by their allelic designation. Thus, the first generated transgenic line [TG(pax6-DF4::M-CFP)Q01] is referred to as line Q01. In most of the lines (eight out of 11), fluorescent protein expression was confined to the retina (Fig. 2A,C), similar to the original GFP lines. As expected, some lines exhibited sparse labeling (e.g. lines Q08, Q11, Q14) and were exploited to follow the behavior of individual amacrine cells (Fig. 2B,D). However, as the number of cells labeled in an individual embryo varied, on average >20 animals had to be screened to obtain embryos with such isolated cells. In all the retina-specific transgenic lines, fluorescent protein expression in the retina was first apparent in neuroblasts by 24 hpf. Starting on the second day and persisting into adulthood, expression became confined to amacrine cells, with somata in the inner nuclear layer (INL) and neurites ramifying in the IPL (Fig. 2B,D).
In three lines, CFP expression was ubiquitous (e.g. line Q01; Fig. 2E). These lines proved useful as a tool to visualize the general organization of the developing retina. The membrane targeting of CFP resulted in the neuropil-rich plexiform layers being densely labeled, and the soma-rich nuclear layers only outlined (Fig. 2F). By crossing ubiquitously expressing CFP fish with amacrine-specific GFP or YFP lines, we were able to monitor the behavior of individual amacrine cells at defined locations within the retina.
Early amacrine cells show undirected process outgrowth
We imaged embryos as early as 41 hpf to capture the behavior of amacrine
cells prior to their arrival at the interface with the nascent IPL. During
migration, amacrine cell processes did not appear to be polarized towards
their eventual target, the IPL (n=5 cells). Instead, they had
multiple processes emerging from their cell body that were highly dynamic
(Fig. 3). Extensive process
outgrowth from amacrine cells thus occurs well before these cells reach their
final somal positions.
|
Amacrine cells polarize by the relative stabilization of GCL-directed processes
Given the multipolar exploration exhibited by these processes, we next
asked whether amacrine neurites extending towards or away from the GCL
differed in their dynamic behavior in a manner that could explain the eventual
formation of a polarized arbor. We performed quantitative analysis of
time-lapse recordings of individual amacrine cell processes to address this
question. Imaging more frequently (inter-frame intervals of 5-10 minutes;
n=9 cells) revealed that both OLM-directed (n=27 processes)
and GCL-directed (n=25 processes) processes underwent rapid
remodeling with similar extension and retraction rates
(Fig. 5A-C) that reached a
maximum motility rate of 0.96 µm/minute. However, although the overall
growth and retraction rates were similar
(Fig. 5C), we found a
significant difference between the life times of OLM-directed (n=15
processes) and GCL-directed processes (n=17 processes; 6 cells;
Fig. 5D). Of the GCL-directed
processes, 65% persisted for the entire period of recording (30 minutes), in
contrast to only 33% of the OLM-directed processes
(Fig. 5D, P<0.001,
Mann-Whitney rank sum test).
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Amacrine cells recognize sublamina-specific cues in the forming IPL
We next asked what mechanisms amacrine cells use to restrict their arbors
to a particular sublamina within the IPL. Many of the pax6 transgenic
lines we generated have a greater number of amacrine cells stratifying in the
OFF sublamina than in the ON sublamina of the IPL at maturity. Thus, most of
our observations are restricted to amacrine cells that stratify in the outer
sublamina of the IPL. We followed individual GFP+ or
YFP+ amacrine cells (n=18 cells) from the time they first
extended lateral arbors within the IPL (demarcated by the ubiquitous membrane
labeling of CFP line Q01) until they had established monostratified arbors
between 70-73 hpf, when sublamination is evident
(Kay et al., 2004). From the
earliest time points, the neuritic arbors of all cells followed were heavily
biased to the outer half of the IPL, where they would ultimately stratify (see
examples in Fig. 7A,B).
Morphometric analysis was used to quantify this bias. We divided the depth of
the IPL into an outer and an inner half, and measured the contribution of
amacrine neurite-derived fluorescence to each half at two time-points, early
(57-62 hpf) and at maturity (70-72 hpf). We found an overwhelmingly high
percentage of neurite-derived fluorescence in the outer half of the IPL at
both time points (99.4% at 57-62 hpf and 98.4% at 70-72 hpf, n=10
cells; Fig. 7C). This bias was
maintained despite growth in the thickness of the IPL over time (from 10 µm
at 57-59 hpf to 14.5 µm at 70-71 hpf, averaged across five retinae) and
lateral expansion of the neuritic arbors.
|
The mechanisms of neurite elaboration into OFF and ON IPL sublaminae could
differ. Although we found an early bias of OFF amacrine cells for the outer
IPL, it is the first sublamina that amacrine cell neurites encounter by virtue
of their somal position in the INL. This left open the possibility that
stratification in the inner half of the IPL (ON sublamina) required exuberant
growth. We managed to observe a small number of amacrine cells that eventually
stratified in the ON sublamina (n=8 cells). We monitored
GFP+ cells in the background of the ubiquitously-expressing CFP
line Q01 (Fig. 8A) or
CFP+ cells in the background of a larger population of
GFP+ amacrine cells (line 220) known to stratify in OFF and ON
sublaminae (Fig. 8B)
(Kay et al., 2004). For these
cells, no exuberance into outer, and thus `inappropriate', IPL sublaminae was
observed, even at early time points (52-58 hpf). Instead, the immature
neurites appear to directly grow towards the inner half of the IPL and spread
laterally upon reaching their appropriate lamina
(Fig. 8A,B).
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Discussion |
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The environment around amacrine cells appears to be uniformly permissive for neurite outgrowth. We found that neurites can extend from their cell bodies in any direction for a protracted period even after their somata have reached the forming INL. However, amacrine neurites directed towards the GCL appear to encounter cues that encourage further elaboration within the IPL; these processes persist for longer periods than neurites directed elsewhere.
The selective elaboration of amacrine neurites within appropriate ON or OFF
sublaminae in the IPL suggests the presence of sublamina-specific cues. We
think that direct cell-cell interactions, rather than molecular gradients, are
the more likely candidates for such cues. This is because, compared with other
CNS regions in which molecular gradients set up specific axonal arborization
patterns (e.g. the tectum or superior colliculus), the IPL is relatively thin
and compact. In the superior colliculus, for example, ephrin gradients extend
over several millimeters along the anteroposterior and mediolateral axes to
help create retinotopic maps (Brown et al.,
2000; Feldheim et al.,
2000
; O'Leary and McLaughlin,
2005
). In the IPL, such molecular gradients would need to be very
steep to set up not only the ON and OFF sublaminae, but also the multiple
strata that lie within each sublamina, as they are only micrometers apart
(Wassle and Boycott, 1991
;
Werblin et al., 2001
).
|
As a result of the sequence in which neurogenesis proceeds in the retina,
the earliest population of differentiated amacrine cells arrives at the
interface of an already formed GCL (see Fig. S1 in the supplementary
material). Although ganglion cells do not appear to be essential for the
stratification of amacrine cells within the ON and OFF sublaminae
(Gunhan-Agar et al., 2000;
Kay et al., 2004
;
Williams et al., 2001
), an
early role for ganglion cells in the orientation of amacrine neurite outgrowth
towards the nascent IPL cannot be ruled out
(Kay et al., 2004
). The early
presence of ganglion cells permits potential contact between their dendrites
and the amacrine processes. These interactions could help to localize the
elaboration of amacrine cell arbors to the nascent IPL.
An alternative substrate for the initial targeting of amacrine neurites
could be displaced amacrine cells. Previous observations from electron
microscopy and Golgi studies of chick, mouse and zebrafish retina suggest that
amacrine cells become displaced by migrating through an already formed IPL to
the GCL (Galvez et al., 1977;
Hinds and Hinds, 1983
;
Schmitt and Dowling, 1999
). By
contrast, our recordings of ptf1a::GFP fish suggest that displaced
amacrine cells and `normally placed' amacrine cells are present concurrently.
The two populations of amacrine cell somata separate by the emergence of
neurites from both populations that are oriented towards each other. Displaced
amacrine cells could thus be a suitable or transient substrate for targeting
by the neurites of `normally placed' amacrine cells, a role not previously
suspected.
Whether by interaction with ganglion cells or displaced amacrine cells, the
earliest `normally placed' amacrine cells form arbors that may be used by
subsequent amacrine cells as scaffolds for stratification. Co-stratification
of newly arriving amacrine cells with previously formed amacrine arbors may
result from their common expression of adhesion molecules. Amacrine cells with
a different complement of adhesion molecules would not be able to co-stratify
with the earliest lamina, but could instead form new laminae either below or
above the earliest strata. In this model, genetically programmed intrinsic
cues would enable amacrine cells to make different laminar choices. Another
possibility is that sublaminae emerge sequentially. A report of the
progressive appearance of axonin 1 immunoreactive amacrine strata in the OFF
sublamina before the ON sublamina is suggestive of such a sequence
(Drenhaus et al., 2004). Such a
sequence may be dictated by the timing of cell birth; cohorts of amacrine
cells born within a particular time window contribute neurites to a common
stratum, and later-generated cohorts establish new strata. In this scenario,
amacrine cells that project to a common sublamina would share common birth
dates. However, birth-dating studies conducted so far suggest that this is
unlikely. Although there is a general sequence in which the different
neurochemical subtypes of amacrine cells are generated [gamma-aminobutyric
acid (GABA)-expressing amacrine cells are generated earlier than cholinergic
and dopaminergic amacrine cells (Evans and
Battelle, 1987
; Lee et al.,
1999
; Reese and Colello,
1992
; Zhang and Yeh,
1990
)], more than one neurochemical type of amacrine cell
innervates a particular sublamina (Drenhaus
et al., 2004
).
Finally, amacrine cells may not only provide laminar cues for each other,
but also for other retinal neurons. The finding that some classes of amacrine
cells stratify before ganglion cell dendrites
(Bansal et al., 2000;
Gunhan et al., 2002
;
Reese et al., 2001
;
Stacy and Wong, 2003
) suggests
that they might provide lamination cues for ganglion cells. Although the
proper stratification of bipolar cell axon terminals after pharmacological
ablation of amacrine cells was taken to suggest that amacrine cells do not
instruct bipolar cell stratification, only cholinergic amacrine cells were
ablated in this study (Gunhan et al.,
2002
). This leaves open the possibility that other amacrine cells
provide laminar cues for bipolar cell stratification. Our previous findings in
lakritz, a zebrafish mutant in which ganglion cells are never
generated, lend strong support to the possibility that amacrine cells instruct
bipolar cell stratification. Amacrine cell sublaminae form properly in this
mutant, except for in some focal regions. Bipolar cells stratify appropriately
except in those local regions where amacrine cell stratification is perturbed
(Kay et al., 2004
). Thus,
amacrine cells may be the primary organizers of sublamination in the IPL.
Indeed, it raises the possibility that interneurons throughout the CNS may
play central roles in the organization of circuitry. Such a role has been
proposed for a population of GABAergic interneurons and Cajal-Retzius cells in
the hippocampus, which, by virtue of their early arborization, guide the
targeted ingrowth of afferents from other hippocampal areas
(Super et al., 1998
). In
contrast to these hippocampal interneurons however, amacrine cells are not a
transient population that exist only to serve as guides. Time-lapse studies in
which amacrine cells and their synaptic partners are simultaneously visualized
would help to clarify their primary role in synaptic targeting within the
IPL.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/22/5069/DC1
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