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First published online 14 June 2006
doi: 10.1242/dev.02430
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Institute for Adaptive and Neural Computation, School of Informatics, University of Edinburgh, 5 Forrest Hill, Edinburgh EH1 2QL, Scotland, UK.
e-mail: willshaw{at}inf.ed.ac.uk
Accepted 8 May 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Retinotopy, EphA receptors, Knockin/knockout, Induction, Quantitative model
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Sperry, 1963;
Sakaguchi and Murphy, 1985;
Stuermer, 1988). It is not
known how such maps are formed, but two main classes of map-making mechanism
have received particular attention (for reviews, see
Goodhill and Richards, 1999;
Price and Willshaw, 2000).
Activity-independent versus activity-dependent mechanisms
According to an activity-independent mechanism involving molecular
recognition, each retinal ganglion cell (RGC) carries information about the
position of its cell body within the retina in the form of a molecular label,
and these labels are used to establish the map. Most detailed proposals of
this type are based on the doctrine of chemoaffinity
(Sperry, 1963), initially
formulated for the retinotectal system, whereby the axon of each labelled RGC
makes a connection with the tectal cell carrying the matching label. The
various mechanisms proposed differ according to the ways in which they have
been applied to maps obtained under normal and contrived situations, which
demonstrated that retinal axons can project to areas other than those to which
they project in the normal, adult projection
(Gaze, 1970;
Gaze and Keating, 1972;
Sharma, 1972;
Gaze et al., 1974;
Straznicky et al., 1981).
An activity-dependent mechanism provides a way of connecting neighbouring
retinal cells to neighbouring tectal cells. The general idea is that
simultaneously active neighbouring cells will be more active than
simultaneously active non-neighbours
(Willshaw and von der Malsburg,
1976). If nerve connections are modified according to the degree
of neural activity in the participating cells
(Hebb, 1949), the connections
between retinal neighbours and tectal neighbours will be strengthened
preferentially.
One widespread view of how neural maps are formed is that an
activity-independent mechanism sets up the map in sufficient precision to
specify the correct polarity of the map. The detailed order within the map is
then developed by means of an activity-dependent mechanism involving
correlated neural activity (Fawcett and
O'Leary, 1985; Schmidt and
Eisele, 1985; Debski and Cline,
2002; Ruthazer and Cline,
2004). However, a lack of detailed experimental evidence has made
it difficult to assess the relative importance of activity-dependent and
activity-independent mechanisms. An evaluation is now possible because of the
recent discovery of molecules that could act as molecular labels, coupled with
the very recent findings of consistent abnormalities in retinocollicular maps
in mouse formed by genetic manipulation of the putative labels
(Brown et al., 2000;
Feldheim et al., 2000;
Reber et al., 2004).
Eph receptor tyrosine kinases are found within the ganglion cells of the
vertebrate retina. Their associated ligands, the ephrins, are found in optic
tectum (fish, frog and chick) and in superior colliculus (mouse)
(Cheng et al., 1995;
Flanagan and Vanderhaeghen,
1998). EphA receptors are distributed in a single continuous
gradient across the nasotemporal axis of the retina; ephrinAs form a similar
gradient across the rostrocaudal axis of the target (tectum or colliculus), to
which the nasotemporal axis projects. Correspondingly, there is a single
gradient of EphB receptor across the dorsoventral axis of the retina and a
gradient of ephrinB across the mediolateral axis of the target
(Hindges et al., 2002;
Mann et al., 2002). In the
normal map, RGCs with high levels of EphB project to target cells with high
ephrinB, and RGCs with low EphB project to cells with low ephrinB. Conversely,
RGCs with high EphA project to cells with low ephrinA, and
vice versa. There is also evidence that ephrins are found in the retina and
Ephs in the tectum or colliculus (Drescher
et al., 1997; McLaughlin and
O'Leary, 2005; Rashid et al.,
2005).
The most quantitative characterisation of the distributions of Ephs or
ephrins in the visual system has been done in the mouse. Mouse retina contains
EphA4, EphA5 and EphA6 receptor types. The densities of EphA5 and EphA6
increase from nasal to temporal retina, whereas that of EphA4 remains
constant. The summed density of all three receptors increases monotonically
from nasal to temporal retina (Reber et
al., 2004).
Scope of the paper
I present my analysis of the class of retinocollicular maps in mouse in
which the normal distribution of EphA receptors within the retina has been
changed by knockin and knockout manipulations
(Brown et al., 2000;
Reber et al., 2004). From my
analysis, I propose that in the development of the ordered map, retinal axons
become arranged over the colliculus according to the molecular labels (assumed
to be the Eph receptors) that they carry. I show that the general form of
these maps is predicted from the marker induction model
(von der Malsburg and Willshaw,
1977; Willshaw and von der
Malsburg, 1979).
In order to investigate how to apply this model in detail to these and related experimental findings, I developed a more specific version of the model, called the retinal induction model, in which the effects of the putative labels, Ephs and ephrins, are represented directly. I present a series of novel computer simulation results.
I present a number of predictions that can be made from the retinal induction model. These are based on the fact that, according to the model, abnormal distributions of label in the retina lead to abnormal distributions of label over the target.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The more rostrally located map is the projection from the
EphA3+ RGCs, both maps being internally ordered along the
rostrocaudal dimension (Fig.
1).
The experimental data analysed here is derived from these experiments
(Brown et al., 2000), together
with a further set of experiments combining the knockin of the EphA3 receptor
into 50% of the RGC population with the knockout of the EphA4 receptor, which
affects all RGCs (Reber et al.,
2004). This gives six different cases: homozygous or heterozygous
EphA3 knockin without EphA4 knockout (##/++, #+/++); homozygous or
heterozygous EphA3 knockin with heterozygous EphA4 knockout (##/+ -, #+/+ -);
homozygous or heterozygous EphA3 knockin with homozygous EphA4 knockout (##/-
-, #+/- -).
In normal retina, the distribution of total EphA receptor density across
the nasotemporal axis can be described mathematically by an exponential
function plus a constant (Reber et al.,
2004). The same mathematical function describes the two EphA
density distributions in each of the six experimental cases. The value of the
constant for the EphA3- cells is different for the
EphA3+ cells. It also depends on which genetic manipulation was
performed: the effect of EphA3 knockin is to increase the value of the
constant from its normal value for the EphA3+ cell population only;
the effect of EphA4 knockout is to decrease its value for both populations.
Changes due to a homozygous knockin or knockout are twice that for a
heterozygous knockin or knockout. The relations between receptor density and
distance along the nasotemporal axis for each of the six cases are given in
Fig. 2, taken from Reber et al.
(Reber et al., 2004).
Methods for the computational modelling
I now describe the marker induction model
(von der Malsburg and Willshaw,
1977; Willshaw and von der
Malsburg, 1979), which was conceived to apply to a wide range of
experimental data known at the time concerned with the development and
regeneration of ordered maps of connections between retina and optic tectum in
non-mammalian vertebrates. Firstly I summarise the original model and then I
introduce a more specific version of the model in which the properties of the
Ephs and ephrins are represented directly. This new model was applied to the
knockin/knockout results described here.
The marker induction model was chosen for consideration here as it is one of the few chemoaffinity-based models that proposed a specific way by which the labels would change in the experimental situations studied. It is assumed that the retinal labels are fixed and the tectal labels can change. Initially the tectal cells are unlabelled (or have weak gradients of label that are easily overwritten) and there is an initial pattern of retinotectal connections that is very diffuse. Several interlinked processes then take place to determine the final pattern of tectal labels and the final retinotectal map: (1) retinal labels are continually transferred into the tectum, through the synapses already formed, where they label the tectum (the rate of transfer into a tectal cell is determined by the total amount of retinal label present in the terminals of the axons impinging on that cell, each contribution from an individual axon being weighted by the strength of the appropriate connection); (2) tectal labels spread out into neighbouring tectal cells; (3) synaptic strengths are continually updated according to how similar the labels in the retinal cell are to the labels in the tectal cell.
By these means, the labels on each tectal cell come to resemble the labels in the cells in a small circumscribed area of retina, so defining a one-to-one mapping between retina and tectum. Introduction of an initial bias, either through the initial pattern of connectivity or through initial weak tectal labels, enables the various part-maps to be aligned in the desired orientation, resulting in an ordered map of connections. With the development of this map, a copy of the retinal labels has become induced into the tectum.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There are marked differences between the maps from homozygous and
heterozygous knockins (Reber et al.,
2004). In the homozygous knockin, the two maps are clearly
separate and each occupies approximately half of the rostrocaudal extent of
the colliculus (Fig. 4A,C,E).
In the heterozygous knockin, the two maps can occupy different unequal extents
of the colliculus and tend to coalesce in rostral colliculus, temporal RGCs
projecting to a single area of colliculus
(Fig. 4B,D,F).
These differences can be related to the degree of overlap between the range of variation of EphA density within the EphA3- population of RGCs compared with the range within the EphA3+ population. As shown in Fig. 2, the overlap for the homozygous knockins is very much less than that for the heterozygous knockins. This suggests that the precise form of these discontinuous maps can be understood by studying the details of the distributions of EphA over the two populations of retinal cells, for each of the experimental cases.
I follow Brown and co-workers (Brown et
al., 2000) in assuming that the value of the label of a collicular
cell is determined by its total EphA density. I used the relation between EphA
receptor density and retinal position
(Reber et al., 2004) to
construct maps of receptor density, rather than retinal position, in the axons
projecting to the colliculus. Fig.
5A-F shows that the graded variation in total EphA density across
the RGCs is recreated within the pattern of terminations of these cells across
the superior colliculus. Regardless of the actual numerical values of EphA
receptor density of individual axons, axons with greatest EphA density project
rostrally and those with least density project caudally. This result, seen in
all six experimental cases, suggests strongly that the mechanism that arranges
the projection of RGCs from across the nasotemporal extent of the retina onto
positions across the rostrocaudal axis of the colliculus involves a sorting
out of retinal axons according to the amount of label, in the form of the
density of EphA in their axons that they carry.
Results from the computational modelling
First of all I illustrate the properties of the retinal induction model
using computer simulation results. I then go on to apply the model to the
series of EphA knockin/knockout results discussed here.
The normal map
Map polarity specified by incoming fibres
I had to check whether in the model one label type per spatial dimension is
sufficient to develop maps between two-dimensional structures, especially when
the EphA and the EphB receptors upregulate the ephrinAs and the ephrinBs in
different ways. Fig. 6 shows
the simulated development of retinotectal connections in Xenopus
laevis (Gaze et al.,
1974). Cells are added to the retina at the periphery and to the
tectum in a rostrolateral-to-caudomedial direction, and so this example also
tests the capacity for tectal cells to be relabelled in response to the
addition of new cells during development
(Straznicky and Gaze, 1971;
Straznicky and Gaze, 1972).
There are no labels in the tectum initially, and the polarity of the map is
determined by the very approximate order within the incoming fibres. The shift
in the map over time is indicated clearly in column four of
Fig. 6 by the movement of the
red disc marking the projection of the oldest retinal cell. The green disc
marks the projection of the most dorsotemporal retinal cell (which should
project to the rostrolateral corner of the tectum), thus indicating that the
desired orientation has been attained. It is also verified that modification
of a single set of synapses suffices to enable a gradient of ephrinB to emerge
in the tectum, which is a direct copy of the EphB gradient in the retina,
while at the same time the ephrinA gradient that emerges is the inverse copy
of the retinal EphA gradient.
Map polarity specified by weak pre-existing concentration gradients
I then carried out simulation experiments to investigate the development of
maps when the polarity of the map is specified by initial weak gradients of
ephrinA and ephrinB over the target structure instead of through the initial
arrangement of retinal fibres arriving at the target. I studied the
development of maps between a full-size simulated retina and a full-size
simulated tectum or colliculus. As the map develops, these initial target
labels are overwritten (Fig.
7A). For comparison, Fig.
7B shows the development of a disordered map in the absence of any
map polarity cues, with random initial connectivity and random initial
distributions of ephrins.
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; McLaughlin and O'Leary,
2005; Rashid et al.,
2005). To demonstrate the flexibility of the model, I show how the
finding that the EphA7 receptor is distributed in graded form over the
rostrocaudal axis of mouse colliculus, with high EphA7 in rostral colliculus
and low EphA7 in caudal colliculus (Rashid
et al., 2005), can be incorporated. A basic assumption of the
model is that ephrinA is upregulated by EphA in such a way that high EphA
leads to low ephrinA, and vice versa. This means that the high-to-low graded
distribution of EphA7 over the rostrocaudal axis of the colliculus will act so
as to reinforce the low-to-high distribution of ephrinA in the same
direction. In the model, the precise effect of counter-gradients of EphA in the colliculus depends on whether the effect is temporary or permanent.
Temporary action
If the EphA7 receptors act only during the initial stages of map
development, effectively the EphA7-derived ephrinAs will enhance the initial
weak ephrin gradients. We can then regard the polarity of the map as being
specified partly by the initial ephrinA gradient and partly by the initial
EphA7 gradient. Removal of the EphA7 contribution makes the map polarity cues
weaker, which can result in distortions to the map or a lack of map alignment
in the correct direction. As the cues get weaker, the map gets more
disorganised; the extreme case of no polarity cues is shown in
Fig. 7B.
Permanent action
One way in which the EphA7 gradient can have an ongoing effect throughout
development is to regard the supply of available EphA7 as an extra input to
each collicular cell, in addition to the supply provided in the incoming
retinal fibres (Fig. 8A). It is
as though, throughout development, the label supplied to each collicular cell
has a fixed, as well as a variable, component. Removal of the EphA7 gradient
(or weakening the input from the retinal fibres) can lead to distortions in
the map, as when a temporary action is assumed; enhancement of the EphA7
gradient can lead to a systematic distortion of the map once the fixed
component of the collicular label predominates
(Fig. 8B).
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Map precision
To provide quantitative measures for the precision of the map, it was
necessary to calculate two quantities: the mean receptive field size of
individual collicular cells (field size) and the mean separation of
receptive field centres (field separation) from neighbouring
collicular cells. To attain ordered maps, both measures must be at least as
small as the mean distance between neighbouring RGCs. In the development of
ordered maps (Fig. 7A,
Fig. 8A), field separation
decreases quickly (Fig. 9A,C),
but it is not until field size also reduces to a near optimal figure that the
maps become ordered; in the development of the disordered map
(Fig. 7B), the projection
shrinks rapidly then expands as both measures re-attain their initial high
level (Fig. 9B); for the
partially ordered map (Fig.
8B), the receptive fields stay high, whereas the field separation
decreases, staying significantly larger than the optimal
(Fig. 9D).
These results confirm that the maps reach a stable state and that the precision attained in the ordered map is not far short of the optimum. Note that there is still substantial overlap in the receptive field or, equivalently, a substantial overlap of retinal arborisation on the colliculus. The limit of precision in the map is controlled by the sensitivity of cells to respond to small fluctuations in Eph and ephrin density; increasing the numbers of cells maintains the values of these precision measures at around the mean spacing between retinal cells, thereby increasing the precision in the map.
EphA knockin/knockout maps
The qualitative model
In all maps, whether normal or abnormal, an induction model predicts that
there will be a single graded distribution of ephrinA across the rostrocaudal
axis of the colliculus. This is matched by a graded (but inverted)
distribution of EphA receptors in the axonal terminals along this axis of the
colliculus (Fig. 10). In
normal animals, this distribution of receptor in the terminals of the axons
spreads over the colliculus matches a similar graded distribution of EphA
receptors in the RGCs along the nasotemporal axis of the retina, meaning that
the retinotectal map is ordered. However, in knockin/knockout animals, because
the EphA3 receptors are distributed across the retina as two interleaved
gradients rather than as a single gradient, there will not be the same
correspondence and the map so defined will be abnormal
(Fig. 10B). As illustrated for
the homozygous knockin map (Brown et al.,
2000), the following key features are predicted: the
EphA3+ cells and the EphA3- cells each make their own
ordered map, in the normal orientation, on distinct areas of the colliculus.
The map made by the EphA3+ cells is situated rostrally and the map
by the EphA3- cells is situated caudally.
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I then simulated each of the six different experimental cases that combine knockin of EphA3 with knockout of EphA4, labelling the retina using the appropriate functions describing EphA receptor density of the retina given in Fig. 2. The plots of the one-dimensional projection of nasotemporal retina to rostrocaudal colliculus (Fig. 4G-L) reproduce the salient features of the maps shown in Fig. 4A-F. There are two separate maps across the tectum, the population of EphA3+ cells projecting more rostrally. The maps are more separated for the homozygotes than for the heterozygotes. Most critically, when collicular position is plotted as a function of EphA density, in all cases there is a graded variation of EphA over the population of axons projecting from caudal to rostral extent of the colliculus (Fig. 5G-K). The main differences between the experimental and simulated connectivity plots are seen in Fig. 4D,F compared with Fig. 4J,L. These could be caused by a variety of factors, such as the nature and extent of the interactions within the colliculus assumed in the model or the relatively small number of retinal and collicular cells simulated; from the experimental side, it is not known how many RGCs are EphA3+ compared with EphA3-, and there is an imprecision in the labelling of retinal fibres when constructing the connectivity map.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Reber et al.,
2004). I have shown that whereas in each case the overall map is
discontinuous and apparently without a meaningful pattern, the distribution of
EphA receptors within the retinal axons distributed across the rostrocaudal
axis of the colliculus forms a single monotonically rising profile. This
pattern is independent of the actual maximum and minimum densities of EphA
receptor within the population of axons, which vary between the different
experimental cases. Given that in normal maps there is an ordered projection
of the nasotemporal axis of the retina onto the rostrocaudal axis of the
colliculus (Simon and O'Leary,
1992), a similar gradient of EphA among the axons innervating the
colliculus occurs there too.
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The role played by retinal labels
These findings of the functional importance of retinal labels is supported
by a vast amount of older, indirect, evidence from the projections formed by
various types of so-called compound eyes in Xenopus laevis. Compound
eyes are constructed by fusing together, in the embryonic eye cup, two
half-eye rudiments of known origin (Gaze
et al., 1963). The eye develops apparently normally, with a single
optic nerve that projects to the contralateral optic tectum, but the
retinotectal map is abnormal. Depending on its retinal origin, each half-eye
projects on to the tectum in order and in a predictable orientation. In some
cases, each of the two half-eyes projects to one half of the tectum
(Gaze and Straznicky, 1980);
in others, each half-eye projects to the whole of the tectum to give a double
map (Gaze et al., 1963;
Straznicky and Gaze, 1980;
Fawcett and Willshaw, 1982).
Some maps are continuous and some discontinuous
(Gaze and Straznicky, 1980;
Straznicky and Gaze, 1980). In
all these various cases, regardless of the actual positions of the parent
cells within the compound eye, axons from RGCs with the same retinal origin
before transplantation to form the compound eye project to the same region of
tectum, and axons of cells with different retinal origins project to spatially
distinct regions of the tectum. These findings suggest strongly that the
retinal cells themselves contain a memory of their original location within
the eye, which is expressed in the map that they form. In other words, retinal
cells carry labels that are used to form the retinotectal map and that remain
fixed after surgical intervention. This conclusion is compatible with a
further set of experimental findings of maps formed by pie-slice compound eyes
(Willshaw et al., 1983). Here,
a small portion of the retinal rudiment was replaced by a similarly sized
portion from another retina that duplicated part of the host part of the
compound eye. In these cases, corresponding part-duplicated maps were
formed.
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)
concentrated on the effects of the EphA receptor, assumed to act as a retinal
label. It was shown that EphA3+ and EphA3- RGCs from the
same retinal location can innervate the same region of colliculus provided
that the ratio of their respective EphA densities is less than
1.36/1. It was therefore suggested that each axon can measure the
ratio of the maximal EphA density in the retina compared to its own EphA
density and that these normalised densities are then used as labels to
determine the relative ordering of axons on the target. It was suggested that
a mechanism based on that proposed by Prestige and Willshaw
(Prestige and Willshaw, 1975)
could act. According to this proposal, both retinal axons and target cells are
graded according to their affinities to make connections: the most affine
retinal axon connects to the most affine target cell, the second-most affine
axon to the second-most affine target cell, and so on. Regardless of the
actual values of the affinities, an ordered map will be produced, provided
that there is a limit to the number of connections that can be made, to
prevent the most affine axon and target cell from dominating. As it stands,
this proposal is incomplete, as in addition a mechanism is required to allow
for the spreading of ordered connections seen in many experimental cases
(Gaze and Keating, 1972). In
addition, the question arises of why ratios have to be measured, given that
the mechanism examined by Prestige and Willshaw
(Prestige and Willshaw, 1975)
could operate on the raw values of EphA density; a computational model would
help clarify these points.
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) developed further the arrow model
(Hope et al., 1976;
Overton and Arbib, 1982),
according to which axons terminating near to each other on the target can swap
over positions if they are the wrong way round. It was assumed
(Koulakov and Tsigankov, 2004)
that Eph receptors label the retina and ephrins label the target, through
graded distributions of these molecules over the two structures. Axons then
use knowledge of the local gradients of the distribution of label over the
target to compute whether they have to interchange their positions. It was
shown that both types of map seen in the EphA3 knockin experiments
(Brown et al., 2000) can be
generated by such a mechanism, provided that the Eph and ephrin profiles are
chosen carefully.
Honda (Honda, 1998;
Honda, 2003) assumed that
there is a single monotonic distribution of EphA receptor across the
nasotemporal axis of the retina and a similar distribution of ephrinA across
the rostrocaudal axis of the colliculus. To account for the fact that high
EphA maps to low ephrinA, and vice versa, it was assumed that a retinal axon
seeks out and contacts with the target cell for which the product of the
retinal receptor density and target ephrin density is a constant. To account
for the EphA3 knockin experimental results
(Brown et al., 2000), an
additional mechanism allowed for repulsion between axons terminating in areas
of the target with a high axonal density, with the result of equalising axonal
density over the entire target.
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) proposed a mechanism involving a combination of attraction
and repulsion between axons and between target cells, coupled with a mechanism
for axonal branch formation that is driven by patterned neural activity.
All three models have been applied to the homozygous and heterozygous
knockin experiments reported in Brown et al.
(Brown et al., 2000). As they
predate the work of Reber et al. (Reber et
al. 2004), they have not yet been applied to the six experimental
cases described here.
Labels in the target depend on those in the retina
To my knowledge, the marker induction class of model is the only proposal
in which the lability observed in the connection patterns is attributed to
changes in the labels within the target structure.
According to this model, once labels become assigned to the retina, they do not change as the map develops or after surgical intervention. The labels in the target (tectum or colliculus) are modifiable, by the labels carried by the retinal axons through interactions at the target.
The original papers describing the marker induction model
(von der Malsburg and Willshaw,
1977; Willshaw and von der
Malsburg, 1979) demonstrated how ordered maps of connections could
be formed between one-dimensional structures in which a large number of
molecular labels was used.
The retinal induction model embodies the marker induction model brought up to date in the light of recent biological data. Here I present several novel results.
Implications for future work
At the general level
Given that a mechanism involving interactions between labelled retinal
axons is sufficient to form a retinotopic map, what is the role of neural
activity in map-making? If electrical activity is involved, the existence of
discontinuities in otherwise ordered maps, such as those seen in the EphA
receptor knockin/knockout maps discussed here
(Brown et al., 2000;
Reber et al., 2004), and also
those in several types of compound eye map
(Gaze and Straznicky, 1980;
Straznicky and Gaze, 1980),
means that this cannot be through the use of correlated neural activity to
ensure that neighbouring retinal cells connect with neighbouring cells in the
target.
There is evidence that knockout of the ß2 nicotinic receptor
eliminates retinal electrical waves and prevents ordered retinotectal map
formation (McLaughlin et al.,
2003). It is possible that there is a causal link between wave
activity and map formation, but currently this is unproven, as other cellular
events that are more closely related to map formation may be disturbed by this
knockout experiment. Much of the evidence that has accumulated for how neural
activity can influence the formation of topographically ordered maps of nerve
connections (Fawcett and O'Leary,
1985; Schmidt and Eisele,
1985; Debski and Cline,
2002; Ruthazer and Cline,
2004) has centred on the effects of abnormal patterns of neural
activity; for example, after activity block using tetrodotoxin
(Stuermer, 1990;
Gnuegge et al., 2001) or NMDA
receptor block using AP5 (Cline and
Constantine-Paton, 1989). A parsimonious view for the involvement
of neural activity is that, rather than refining an initially coarse map set
up by chemoaffinity, it acts later on in development, once the precision of
the map has been established. Its primary role would be to prune away the
axonal arbor so as to reduce the overlap between adjacent axonal projections
(Johnson et al., 1999;
Ruthazer and Cline, 2004). In
the special case of the double innervation of the target, in either the
three-eyed frog (Constantine-Paton and Law,
1978), Xenopus compound eye
(Fawcett and Willshaw, 1982)
paradigms or by allowing optic nerve fibres to reinnervate both contralateral
and ipsilateral tecta (Law and
Constantine-Paton, 1980;
Meyer, 1982), this will result
in the formation of striped patterns of ocular dominance. On this
interpretation, it would be expected that, in the three heterozygous EphA3
knockin cases discussed here, eventually discontinuous projections would
develop on the rostrocaudal region of colliculus where coalescence of the
projections from EphA3+ cells and EphA3- cells was
observed. Relevant here is that in ordered maps produced in the model (e.g.
Fig. 7A), there is still
substantial overlap of receptive field sizes and therefore retinal
arborisations, in the final stable maps (e.g.
Fig. 9A).
The specific mechanism proposed here involves the upregulation of labels in
the target cells by the labels carried by the retinal axons. More direct
evidence relating to this point is needed. In goldfish, upregulation of
ephrins coincides with reinnervation of the optic tectum
(Rodger et al., 2000), but
this does not occur in frog (Bach et al.,
2003).
At the specific level: the nature of the labels used
The retinal induction model has been defined in sufficient detail for the
retinotectal or retinocollicular connectivity pattern to be predicted from a
knowledge of a given distribution of gradients of Ephs and ephrins labelling
the retina and the tectum or colliculus. This suggests new experiments and
interpretations.
), it would
be worth investigating the consequences of relaxing this restriction. To
enable this to be done satisfactorily, additional experimental evidence is
required, particularly concerning the numbers and distributions of nerve cells
over the target structure. ). This could mean that this knockout manipulation removes the
machinery needed for ephrins to be upregulated under the influence of the Eph
receptors in the retinal axons. In addition, or alternatively, it could be
that ephrinA knockout removes the initial weak gradients over the target
(Fig. 11) that determine map
polarity. ) will
result in abnormal types of maps. The precise form of these maps can be
predicted from the model, once there is data about the distributions of EphB
receptor over the normal retina and how these distributions are changed by the
knockin/knockout manipulations. ). The retinal induction model predicts that the
distribution of label across the rostrocaudal axis of the colliculus (which is
assumed here to be ephrinA) will be different for each of the six cases
analysed and will be related systematically to the distribution of EphA
receptor over the population of innervating retinal ganglion cells. |
ACKNOWLEDGMENTS |
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REFERENCES |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Bach, H., Feldheim, D. A., Flanagan, J. G. and Scalia, F. (2003). Persistence of graded EphA/ephrin-A expression in the adult frog visual system. J. Comp. Neurobiol. 467,549 -565.[CrossRef][Medline]
Brown, A., Yates, P. A., Burrola, P., Ortuno, D., Vaidya, A., Jessell, T. M., Pfaff, S. L., O'Leary, D. D. M. and Lemke, G. (2000). Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102,77 -88.[CrossRef][Medline]
Cheng, H. J., Nakamoto, M., Bergemann, A. D. and Flanagan, J. G. (1995). Complementary gradients in expression and binding of Elf-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82,371 -381.[CrossRef][Medline]
Cline, H. T. and Constantine-Paton, M. (1989). NMDA receptor antagonists disrupt the retinotectal topographic map. Neuron 3,413 -426.[CrossRef][Medline]
Constantine-Paton, M. and Law, M. I. (1978).
Eye-specific termination bands in tecta of three-eyed frogs.
Science 202,639
-641.
Debski, E. and Cline, H. (2002). Activity-dependent mapping in the retinotectal projection. Curr. Opin. Neurobiol. 12,93 -99.[CrossRef][Medline]
Drescher, U., Bonhoeffer, F. and Muller, B. (1997). The Eph family in retinal axon guidance. Curr. Opin. Neurobiol. 7,75 -80.[CrossRef][Medline]
Fawcett, J. W. and Willshaw, D. J. (1982). Compound eyes project stripes onto the optic tectum. Nature 296,350 -352.[CrossRef][Medline]
Fawcett, J. W. and O'Leary, D. D. M. (1985). The role of electrical activity in the formation of topographic maps in the nervous system. Trends Neurosci. 8, 201-206.
Feldheim, D. A., Kim, Y.-I., Bergemann, A., Frisen, J., Barbacid, M. and Flanagan, J. (2000). Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25,563 -574.[CrossRef][Medline]
Flanagan, J. G. and Vanderhaeghen, P. (1998). The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21,309 -345.[CrossRef][Medline]
Gaze, R. M. (1958). The representation of the
retina on the optic lobe of the frog. Q. J. Exp. Physiol. Cogn.
Med. Sci. 43,209
-224.
Gaze, R. M. (1970). The Formation of Nerve Connections. London: Academic Press.
Gaze, R. M. and Keating, M. J. (1972). The visual system and `neuronal specificity'. Nature 237,375 -378.[CrossRef][Medline]
Gaze, R. M. and Straznicky, C. (1980). Stable programming for map orientation in disarranged embryonic eyes in Xenopus. J. Embryol. Exp. Morphol. 55,143 -165.[Medline]
Gaze, R. M., Jacobson, M. and Szekely, G. (1963). The retinotectal projection in Xenopus with compound eyes. J. Physiol. Lond. 165,384 -499.
Gaze, R. M., Keating, M. J. and Chung, S. H. (1974). The evolution of the retinotectal map during development in Xenopus. Proc. R. Soc. Lond. B Biol. Sci. 185,301 -330.[Medline]
Gnuegge, L., Schmid, S. and Neuhauss, S. C.
(2001). Analysis of the activity deprived zebrafish mutant macho
reveals an essential requirement of neuronal activity for the development of a
fine-grained visuotopic map. J. Neurosci.
21,3542
-3548.
Goodhill, G. and Richards, L. (1999). Retinotectal maps: molecules, models and misplaced data. Trends Neurosci. 22,529 -534.[CrossRef][Medline]
Hebb, D. O. (1949). The Organization of Behavior. New York: Wiley.
Hindges, R., McLaughlin, T., Genoud, N., Henkemyer, M. and O'Leary, D. D. M. (2002). EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 35,475 -487.[CrossRef][Medline]
Honda, H. (1998). Topographic mapping in the retinotectal projection by means of complementary ligand and receptor gradients: a computer simulation study. J. Theor. Biol. 192,235 -246.[CrossRef][Medline]
Honda, H. (2003). Competition for retinal
ganglion axons for targets under the servomechanism model explains abnormal
retinocollicular projection of Eph receptor-overexpressing or ephrin-lacking
mice. J. Neurosci. 23,10368
-10377.
Hope, R. A., Hammond, B. J. and Gaze, R. M. (1976). The arrow model: retinotectal specificity and map formation in the goldfish visual system. Proc. R. Soc. Lond. B Biol. Sci. 194,447 -466.[Medline]
Jeon, C.-J., Strettoi, E. and Masland, R. H.
(1998). The major cell populations of the mouse retina.
J. Neurosci. 18,8936
-8946.
Johnson, F. A., Dawson, A. J. and Meyer, R. L. (1999). Activity-dependent refinement in the goldfish retinotectal system is mediated by the dynamic regulation of processes withdrawal: an in vivo imaging study. J. Comp. Neurol. 406,548 -562.[CrossRef][Medline]
Koulakov, A. A. and Tsigankov, D. N. (2004). A stochastic model for retinocollicular map development. BMC Neurosci. 5,30 -46.[CrossRef][Medline]
Law, M. I. and Constantine-Paton, M. (1980).
Right and left eye bands in frogs with unilateral tectal ablations.
Proc. Natl. Acad. Sci. USA
77,2314
-2318.
Mann, F., Ray, S., Harris, W. A. and Holt, C. E. (2002). Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrinB ligands. Neuron 35,461 -473.[CrossRef][Medline]
McLaughlin, T. and O'Leary, D. D. M. (2005). Molecular gradients and development of retinotopic maps. Annu. Rev. Neurosci. 28,325 -355.
McLaughlin, T., Torborg, C. L., Feller, M. F. and O'Leary, D. D. M. (2003). Retinotopic refinement requires spontaneous retinal waves during a critical period of development. Neuron 40,1147 -1160.[CrossRef][Medline]
Meyer, R. L. (1982). Tetrodotoxin blocks the
formation of ocular dominance columns in goldfish.
Science 218,589
-591.
Overton, K. J. and Arbib, M. A. (1982). The extended branch-arrow model of the formation of retinotectal connections. Biol. Cybern. 45,157 -175.[CrossRef][Medline]
Prestige, M. C. and Willshaw, D. J. (1975). On a role for competition in the formation of patterned neural connexions. Proc. R. Soc. Lond. B Biol. Sci. 190, 77-98.[Medline]
Price, D. J. and Willshaw, D. J. (2000). Mechanisms of Cortical Development. Oxford: Oxford University Press.
Rashid, T., Upton, A. L., Blentic, A., Clossek, T., Knoell, B., Thompson, I. D. and Drescher, U. (2005). Opposing gradients of ephrin-As and EphA7 in the superior colliculus are essential for topographic mapping in the mammalian visual system. Neuron 47,57 -69.[CrossRef][Medline]
Reber, M., Burrola, P. and Lemke, G. (2004). A relative signalling model for the formation of a topographic neural map. Nature 431,847 -853.[CrossRef][Medline]
Rodger, J., Bartlett, C. A., Beazley, L. D. and Dunlop, S. A. (2000). Transient upregulation of the rostrocaudal gradient of ephrin-A2 in the tectum coincides with reestablishment of orderly projections during optic nerve regeneration in goldfish. Exp. Neurol. 155,196 -200.
Ruthazer, E. S. and Cline, H. T. (2004). Insights into activity-dependent map formation from the retinotectal system: a middle-of-the-brain perspective. J. Neurobiol. 59,134 -146.[CrossRef][Medline]
Sakaguchi, D. S. and Murphy, R. K. (1985). Map formation in the developing Xenopus retinotectal system: an examination of ganglion cell terminal arborizations. J. Neurosci. 5,3228 -3245.[Abstract]
Schmidt, J. T. and Eisele, L. E. (1985). Stroboscopic illumination and dark-rearing block the sharpening of the regenerated retinotectal map in goldfish. Neuroscience 14,535 -546.[CrossRef][Medline]
Sharma, S. C. (1972). The retinal projection in adult goldfish: an experimental study. Brain Res. 39,213 -223.[CrossRef][Medline]
Simon, D. K. and O'Leary, D. D. M. (1992). Development of topographic order in the mammalian retinocollicular projection. J. Neurosci. 12,1212 -1232.[Abstract]
Sperry, R. W. (1963). Chemoaffinity in the
orderly growth of nerve fiber patterns and connections. Proc. Natl.
Acad. Sci. USA 50,703
-710.
Straznicky, K. and Gaze, R. M. (1971). The growth of the retina in Xenopus laevis: an autodioradiographical study. J. Embryol. Exp. Morphol. 26, 67-79.[Medline]
Straznicky, K. and Gaze, R. M. (1972). The development of the tectum in Xenopus laevis: an autoradiographical study. J. Embryol. Exp. Morphol. 28, 87-115.[Medline]
Straznicky, K. and Gaze, R. M. (1980). Stable programming for map orientation in fused eye fragments in Xenopus. J. Embryol. Exp. Morphol. 55,123 -142.[Medline]
Straznicky, K., Gaze, R. M. and Keating, M. J. (1981). The development of the retinotectal projections from compound eyes in Xenopus. J. Embryol. Exp. Morphol. 58, 79-91.
Stuermer, C. A. O. (1988). Retinotopic organization of the developing retinotectal projection in the zebrafish embryo. J. Neurosci. 8,4513 -4530.[Abstract]
Stuermer, C. A. O. (1990). Retinotopic organization of the developing retinotectal projection in the zebrafish embryo under TTX-induced neural-impulse blockade. J. Neurosci. 10,3615 -3626.[Abstract]
von der Malsburg, C. and Willshaw, D. J.
(1977). How to label nerve cells so that they can interconnect in
an ordered fashion. Proc. Natl. Acad. Sci. USA
74,5176
-5178.
Willshaw, D. J. and von der Malsburg, C. (1976). How patterned neural connexions can be set up by self-organisation. Proc. R. Soc. Lond. B Biol. Sci. 194,431 -445.[Medline]
Willshaw, D. J. and von der Malsburg, C.
(1979). A marker induction mechanism for the establishment of
ordered neural mappings: its application to the retinotectal problem.
Proc. R. Soc. Lond. B Biol. Sci.
287,203
-234.
Willshaw, D. J., Fawcett, J. W. and Gaze, R. M. (1983). The visuotectal projections made by Xenopus `pie slice' compound eyes. J. Embryol. Exp. Morphol. 74, 29-45.[Medline]
Yates, P. A., Holub, A. D., McLaughlin, T., Sejnowski, T. J. and O'Leary, D. D. M. (2004). Computational modeling of retinotopic map development to define contributions of EphA-ephrinA gradients, axon-axon interactions, and patterned activity. J. Neurobiol. 59,95 -113.[CrossRef][Medline]
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