Download A FAILURE OF INDUCTION IN NORMAL DEVELOPMENT

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A FAILURE OF INDUCTION IN NORMAL
DEVELOPMENT
BY C. H. WADDINGTON.
(Senior Student of the Royal Commissioners of the Exhibition of 1851.)
(Sub-Department of Experimental Zoology, Cambridge.)
(Received August 12, 1935.)
(With One Text-figure.)
CONTENTS.
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I. Introduction
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I I . C o m p e t e n c e o f lateral e c t o d e r m c o n t e m p o r a n e o u s w i t h i n d u c i n g c a p a c i t y o f
side-plate m e s o d e r m
I I I . General characteristics of a process of induction
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I V . T h e specification of p o i n t s w i t h i n t h e neural p l a t e :
(a) L o n g i t u d i n a l co-ordinates .
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(b) T r a n s v e r s e co-ordinates
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V. T h e failure of evocation outside t h e neural p l a t e :
(«) T h e weakness of t h e evocating powers of t h e side-plate m e s o d e r m
(b) T h e w e a k e n i n g of t h e c o m p e t e n c e of t h e lateral e c t o d e r m .
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Summary
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I. INTRODUCTION.
the neural plate of the Urodele Amphibia has provided the foundation
on which modern experimental embryology has been built, it continues to provide
us with new problems for solution. Soon after Spemann's original demonstration
(1918, 1924) that the neural plate owes its inception to an inducing stimulus provided by the underlying mesoderm, Bautzmann (1926) presented evidence to show
that in the young gastrula the region which is capable of inducing is more or less
the same as the region which eventually comes to lie immediately under the neural
plate. It therefore seemed to be true that in normal development all mesoderm
which is capable of inducing actually does so. But recently facts have emerged
which cast doubt on this simple hypothesis. Holtfreter (1933 a) showed that in
the neurula stage the side-plate mesoderm, which does not underlie the neural
plate, is also capable of inducing the formation of neural tissue in pieces of young
gastrula ectoderm brought in contact with it. Now Machemer (1932), in a very
careful investigation of the variation with age of capacity of gastrula ectoderm to
react to an inducing stimulus, showed that this capacity to react, or competence,
persists till a stage when the side-plate mesoderm is beginning to be formed. It
becomes necessary to inquire whether there is any overlap of the period when the
ALTHOUGH
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side-plate mesoderm can induce with that in which the ectoderm can react, and
if there should be such an overlap, why no reaction actually occurs in normal
development.
II. COMPETENCE OF LATERAL ECTODERM CONTEMPORANEOUS
WITH INDUCING CAPACITY OF SIDE-PLATE MESODERM.
The question was investigated by the following experiment. In a Triton alpestris
gastrula in the medium-sized yolk plug stage, a flap of ectoderm was lifted up near
the ventro-lateral lip of the blastopore, the side-plate mesoderm was carefully
cleaned away from underneath it, and a fragment of the dorsal lip of a young
T. alpestris gastrula was substituted. The side-plate mesoderm obtained in this
way was then implanted into the blastocoele of another young alpestris gastrula.
Owing to lack of material and pressure of other work, comparatively few experiments were made, but the results which were obtained were perfectly clear. Both
the side-plate mesoderm implanted into the young gastrulae, and the dorsal lip
implanted into the old gastrulae, induced the formation of secondary neural tubes.
There is no difficulty in making the grafts into the old gastrulae. In the fixed
and sectioned embryos it can be seen that the graft has developed in accordance
with its presumptive fate into notochord with some somitic mesoderm, as Bautzmann
(1933) has described; the somites were usually very irregularly and imperfectly
formed in my material. The graft mass has usually elongated in the direction of
the host's gastrulation movements; no attempt was made to control the orientation
of the pieces when they were grafted. In several cases the graft is accompanied
throughout its whole length by an induced neural plate or tube, though sometimes
the induced plate is shorter than the graft mass. The graft and induced plate may
lie in the ventro-lateral region of the host, which is where the graft was originally
placed, but in some specimens the graft seems to have been pulled in towards the
dorsal mid-line of the host, carrying with it the induced plate which becomes united
laterally with the host plate. Since the experiments did not involve heteroplastic
grafting, the boundaries of the graft mesoderm cannot be precisely determined,
but, while the graft notochord always remains distinct from the host notochord,
it is clear that some of the graft mesoderm unites with host mesoderm to form
compound, chimaerical somites. Fig. 1 shows outline drawings of the host axis
and the associated induced axis in one specimen of this kind, No. D70D—2. Very
similar embryos have been described by Bautzmann (1933), who exchanged dorsal
and lateral mesoderm in young gastrulae, but in his specimens the graft was
originally made nearer the dorsal mid-line, and the tendency of the host mesoderm
to incorporate the graft was therefore not so obvious. This tendency for the
mesoderm to form a single complete system will be referred to as a function of
the mesoderm individuation field (p. 78). The tendency for two contiguous neural
plates to unite and even to regulate to one single plate is an even commoner and
more striking phenomenon, particularly remarkable examples of which have been
described in the bird embryo (Waddington and Schmidt, 1933). It would well
repay a special investigation.
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In grafting lateral mesoderm into young gastrulae, certain technical difficulties
were met with. The amount of side-plate mesoderm which is obtained while making
a graft into one mid-gastrula is hardly sufficient to make a satisfactory graft, as
the cells hang together only very loosely and some are inevitably lost. It is therefore
necessary to combine material from two or more gastrulae, and considerable care
is required to implant the separate heaps of loosely connected cells so that they
form a single mass lying against the host's ectoderm. In subsequent development,
many of the grafts become entirely lost, either because the grafted cells became
separated or because the mass was small enough to be completely incorporated
into the host's side-plate. In other specimens the graft can be seen as a thickening
Fig. I a.
Fig. ib.
Fig. 1. Embryo No. D70D-2. Diagrammatic sections through the combined host and induced
axes (camera lucida drawing). Fig. in is further posterior than Fig. 16. Neural tissue hatched
with vertical lines, host notochord widely spaced dots, graft notochord closely spaced dots.
of the side-plate of the host; it never shows any trace of development into chorda
or somites. In some cases the graft is accompanied by an induced neural plate or
tube, which may be perfectly normally differentiated. There is a suggestion that
in those specimens in which induction has occurred the graft is less well incorporated than it is in the specimens in which induction has failed to occur,
but the data are not extensive enough to permit of a definite statement to this
effect.
III. GENERAL CHARACTERISTICS OF A PROCESS OF INDUCTION.
The experiments which have been described above show that the two materials
which are capable of reacting together to produce neural tissue both spread out
lateral to the area in which neural plate actually forms. It is therefore impossible
to suppose that the region of ectoderm which becomes the neural plate is the same
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as the area under which there lies inducing mesoderm. If we proceed then to
consider how the shape of the plate is determined, we have first to remember that
the shape in question is continually changing as development proceeds. The series
of three-dimensional configurations assumed by a mass of neural tissue must be
the result of some forces, as to whose nature we are still almost entirely ignorant.
These forces produce in normal development a series of shapes which are characteristic of the well-known morphogenesis of the neural plate; and further, the same
series of shapes is produced even if slight alterations are made in the size or disposition of the mass of tissue which forms the starting point of the development.
In other words, the neural plate, like most other organs, has a certain regulatory
power in the early stages of its development, and the normal series of shapes
assumed by it in the undisturbed development of the embryo can be considered
as a stable equilibrium (which is of course a function of the time, that is, a fourdimensional equilibrium), towards which the system tends to return after being
altered in any way. It is convenient in such a case to refer to neural plate as an
individuation field (Waddington and Schmidt, 1933), the forces concerned in the
equilibrium as the field forces and the laws by which the forces are related and
to which the production of the equilibrium is due as the field laws. The word
"field" is already in use with a large number of meanings; it often seems to be
employed merely to refer to regions whose boundaries are not sharply denned,
and it therefore seems excusable to introduce the special term individuation field
for regions such as we are considering, regions, that is to say, in which forces are
at work moulding the tissue into a definite shape. In what follows the contraction
I.F. will be used for the expression "individuation field".
In considering the determination of the shape of the neural plate, we are then
actually considering the agencies which define the characteristics of the neural
plate I.F. In exactly the same way the whole expanse of the mesoderm is an I.F.,
that is to say it is the site of field forces which tend to produce a series of equilibrium shapes.
We are now in a position to discuss the various processes concerned in this
determination. Firstly, the mesoderm calls the neural plate into being; without
the presence of the mesoderm the neural plate and its I.F. would not be there, as
Holtfreter (1933 b) has finally demonstrated. This process of calling into being,
originally referred to as "induction as such" (Waddington and Schmidt, 1933)
and later as evocation (Needham, Waddington and Needham, 1934), is due to the
diffusion of a chemical substance from the mesoderm into the overlying ectoderm,
as recent research has shown. In the normal development of the chick, this diffusion
does not seem to be regulated by the mesoderm field laws in the dorso-ventral
direction, that is, it is not controlled so as to build up any unit shape, since the
axial mesoderm can evocate a neural tube against its ventral surface even when it is
already in contact with a neural plate lying against its dorsal surface, and it can
thus evocate more neural tissue than is required for the normal equilibrium shape
(Waddington and Schmidt, 1933). The experiment does not seem to have been
performed in the Amphibia, but it is likely that the same conclusion holds there
A Failure of Induction in Normal Development
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also. We shall have to discuss later whether the mesoderm I.F. controls the area
of mesoderm out of which this diffusion can occur.
IV. THE SPECIFICATION OF POINTS WITHIN THE NEURAL PLATE.
(a) Longitudinal co-ordinates.
The neural plate must also be "individuated" (Waddington and Schmidt),
that is, two co-ordinates must be specified for each point, giving its position on
the anterior-posterior and transverse axes (neglecting for the present purposes its
position on the dorso-ventral axis). A process of induction, as opposed to a process
of evocation, must involve the specification of these two sets of co-ordinates. There
are two possibilities; either the co-ordinates are specified by the mesoderm I.F., or
they are previously fixed in the ectoderm, which would then have certain field laws
before the specifically neural plate field laws were evocated in it.
Spemann (1931) has discussed both possibilities with reference to the longitudinal set of co-ordinates, and decided rather in favour of the second. Waddington
and Schmidt (1933), on the basis of work performed on the bird embryo, criticised
Spemann's arguments and favoured the first alternative, and more recently Holtfreter (1934) has supported the same view in connection with the Amphibia.
Possibly the two alternatives are not mutually incompatible, but the experiments
reported in the present communication shed no further light on the determination
of the longitudinal set of co-ordinates.
(b) Transverse co-ordinates.
Our data concern more closely the specification of the transverse co-ordinates.
Two facts emerge from previous work. In the first place, a complete set of transverse co-ordinates can be produced by the ectoderm without the co-operation of
the mesoderm I.F. This is demonstrated by those cases in which a transversely
asymmetrical part of the mesoderm I.F., which moreover remains asymmetrical
during the process, induces a symmetrical neural plate: examples are found in the
work of Holtfreter (1933 a) on induction by side-plate mesoderm in the neurula
stage. The same principle is exemplified in those comparatively few cases in which
a dead organiser, in which the field is presumably destroyed, has evocated a symmetrical neural plate of normal shape in ectoderm which is not connected to the
main axis of an embryo. Even those cases in which a "fieldless" (dead or dissolved)
organiser evocates a symmetrical neural tube in ectoderm which is still part of a
complete embryo may probably be taken to support the same conclusion, since
although the host's mesoderm I.F. might well affect the longitudinal co-ordinates
of the evocated field, it is more difficult to see how it could influence the transverse
co-ordinates.
Although the ectoderm can, as we have just seen, produce a field completely
specified in the transverse direction, other evidence makes it probable that this
specification can also be affected by an underlying mesoderm I.F. The most conclusive evidence comes from the observation of compound neural plates underlain
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and induced by compound, unequilibrated mesoderm fields. If a mass of neural
tissue is induced by two masses of mesoderm which for some reason do not completely attain the unitary equilibrium shape, the neural plate which is formed shows
on the one hand a tendency to form a single unit, which tendency might be attributed to the self-sufficiency of the transverse component of the ectoderm I.F., and
on the other hand a definite doubleness which can only be attributed to the doubleness of the mesoderm I.F. Examples of this are very frequent; one has been
described and figured above and many other examples will be found in the literature;
some particularly striking examples have been described in birds (Waddington and
Schmidt). Other evidence which demonstrates the effect of the mesoderm field in
this respect is derived from those experiments in which the size or specific nature
of the mesoderm I.F. determines the size of the induced neural plate, for instance
in the experiments of Ruud and Spemann (1923) on half-gastrulae and of Holtfreter
(1935) on Anural-Urodele chimaeras. It seems clear then that the transverse component of the neural plate I.F. is determined by a collaboration of the mesoderm I.F.
with a tendency which is already present in the ectoderm and can be released by
the mere process of evocation.
V. THE FAILURE OF EVOCATION OUTSIDE THE NEURAL PLATE.
The final aim must be to discover what is the material basis underlying the
specification of a co-ordinate. We are still far from this goal. The next immediate
step is the investigation of the consequences of any particular specification. Within
the limits of the neural plate itself these consequences are summed up in the results
of morphological and histological, and eventually chemical, examination. But for
the regions lateral to the neural plate we have to consider the further fact, which
is the subject of this paper, namely that there is a failure of evocation.
This failure of evocation cannot be ascribed only to the weakness of the evocating
powers of the lateral mesoderm, since this mesoderm, as has been shown above,
can evocate in young gastrula ectoderm, and should therefore evocate in the lateral
ectoderm which it normally underlies if that ectoderm persists unchanged from
the young gastrula stage. On the other hand, it is equally clear that it is not only
the ectoderm which is at fault, since that same ectoderm can react to a stimulus
as powerful as that of the young dorsal lip. We must assume both that the sideplate mesoderm evocates less strongly than does the young dorsal lip, and that the
lateral ectoderm reacts less readily than young gastrula ectoderm.
(a) The weakness of the evocating powers of the side-plate mesoderm.
There are two main possibilities as regards the evocating power of the sideplate mesoderm; the mesoderm at this stage may be able to exert only a weak
evocating stimulus even under the best conditions, either because only a weak
evocating power has as yet developed or because the evocating power has been
irreversibly affected by the remaining parts of the general mesoderm I.F. ; or the
side-plate mesoderm may be potentially able to exert a strong stimulus which is
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normally controlled and weakened by a reversible action of the general mesoderm
I.F. We have not as yet sufficient data on the evocating powers of the side-plate
mesoderm after isolation from the mesoderm I.F. to give an accurate evaluation of
these two possibilities. The evidence which is available suggests that both may be
to some extent realised. On the one hand, the inductions performed by the sideplate mesoderm, transplanted from the yolk-plug gastrula, have never been as
extensive as the normal inductions by young dorsal lip, which suggests that they
are reactions to a weaker stimulus. It is quite possible that the intrinsic evocating
capacity of the side-plate mesoderm increases rapidly from the young gastrula, in
which Bautzmann (1926) found an almost complete inability to evocate, through
the fairly weak phase of the mid-gastrula, to the strongly acting condition described
by Holtfreter (1933 a) in the neurula. On the other hand, the influence of the
mesoderm I.F. in suppressing evocation is suggested by the observation that evocation is nearly always absent in those cases in which the grafted side-plate mesoderm
has been completely incorporated into the side-plate of the host. A similar suppression by the mesoderm I.F. of a possible evocation certainly occurs in the chick
embryo (Waddington, 1932; Waddington and Schmidt, 1933).
(b) The weakening of the competence of the lateral ectoderm.
For the weakening of the reaction of the ectoderm there are three factors to be
considered. Each individual cell of the ectoderm may become less reactive through
an inherent process, or the reactivity of the lateral ectoderm may be suppressed
by the underlying part of the mesoderm I.F., that is, by the side-plate mesoderm,
or the reactivity may be suppressed by the neural plate field which is gradually
arising; or finally the suppression may be due to some combination of these
factors.
It is easy to make a direct test of the first possibility, and this has been done.
Ectoderm was removed from several young gastrulae (Triton alpestris) and was
then cultivated in Holtfreter solution along with other gastrulae of the same age
until such time as these gastrulae developed open neural plates. Evocating tissue
(archenteron roof from the neural plate embryos) was then implanted into the
isolated ectoderm fragments. In some cases, though not in all, neural tissue was
induced, although it is well known that the ectoderm of the neural plate stage is
normally quite incapable of reacting to the stimulus which evocates neural differentiation. One must conclude that the rapid loss of competence of the ectoderm
between the gastrula and neurula stages is not due to an inherent process, though
there can be little doubt that this competence is eventually lost even in isolated
ectoderm, and the processes which cause this slow loss may have begun to play
some role even before gastrulation is complete.
Returning to the other factors mentioned above, it is easy to see that the mere
presence of side-plate mesoderm cannot alone be the condition responsible for the
suppression of the competence of the lateral ectoderm, since if it were the sideplate mesoderm should not be able to perform evocations in young gastrula ectoderm, as it actually can. We can also exclude the possibility that the loss of
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competence is dependent solely on continued connection with the neural plate I.F.,
since if mid-gastrula lateral ectoderm together with the underlying side-plate
mesoderm is cultivated in isolation from the presumptive neural plate, no neural
evocation occurs. The isolations which were made to test this point were not
cultivated long enough for a complete development of the mesoderm, but there
was every indication that the mesoderm had self-differentiated into its presumptive
fate. In any case, the failure of evocation in this experiment shows that there is
neither an acquirement by the ectoderm of a reactivity as sensitive as that of young
gastrula ectoderm nor an acquirement by the mesoderm of a power of evocation
equal to that of the young dorsal lip. Therefore we can neither attribute the whole
of the loss of competence of the ectoderm to the continued presence of the neural
plate, nor, to return to a subject we have discussed earlier, can we hold the mesoderm
I.F. entirely responsible for the weakness of the evocating capacity of the side-plate
mesoderm, though as we have seen it may have some influence of this kind.
We are left with the alternatives that the side-plate mesoderm is able to suppress
the competence of the lateral ectoderm only while it is still in its place in the whole
mesoderm field, or that in the period between the young and middle gastrula the
ectoderm has been brought, either by virtue of its connection with the developing
neural plate or through inherent change, into a state in which it can react with
the side-plate in such a way as to lose its competence.
We can test the last two of these possibilities by isolating ectoderm and presumptive side-plate mesoderm before the neural plate I.F. has begun to develop.
If it is the neural plate I.F. which brings the ectoderm into a state in which its
competence is suppressed by the side-plate, then the suppression should fail to
occur in the isolates and neural tissue should be developed; while if the preparation
of the ectoderm is done by an inherent process, we would expect to find no neural
tissue. In fact, the ventral half of a young gastrula develops into a " Bauchstuck",
in which the included ventral and lateral mesoderm develops into its presumptive
fate and in doing so does not induce neural tissue. This evidence suggests that the
preparation of the ectoderm is mainly due to an inherent process. But the evidence
from a Bauchstuck cannot be regarded as conclusive, since Mangold and Seidel
(1927) have described the presence of neural tissue in such systems, though they
themselves expressed a doubt as to the validity of their result.
No experiments have yet been made which allow one to evaluate the probability
of the first of the three alternatives mentioned above, namely that the competence
of the lateral ectoderm is suppressed by the side-plate mesoderm only if the
mesoderm remains part of the whole mesoderm I.F.
We are left, then, with three factors which may be invoked to explain the
weakness of the competence of the lateral ectoderm. The first is that the ectoderm
changes, through some inherent process, in such a way that at the mid-gastrula stage
it is in a state in which it reacts with the side-plate mesoderm with a rapid loss of
competence. This inherent process of change might perhaps be connected with
the process which causes the slow loss of competence in isolated ectoderm fragments. The second possibility can only be entertained if we accept the presence
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of neural tissue in a Bauchstuck; it also supposes that the ectoderm is changed
between the young and mid-gastrula stages, but it attributes this change to the
developing neural plate I.F. We have already seen that the developing neural plate
I.F. can specify the transverse set of co-ordinates within the neural plate itself, and
this second hypothesis merely supposes that it can also do so in the regions lateral
to the plate; it supposes, in fact, that the neural plate field is not confined to the
neural plate but extends throughout the whole ectoderm. The third possibility is
that the loss of competence is dependent on the mesoderm I.F., the suppression
actually being carried out by the side-plate mesoderm which forms part of the field.
Again, we have seen that the mesoderm field can specify the set of transverse
co-ordinates of points within the plate, and there seems no theoretical reason why
it should not specify them for points outside the plate.
If we accept this general specification of co-ordinates by the mesoderm, it
becomes considerably easier to understand the peculiar phenomenon of induction
by the so-called "complex situation stimuli". Mangold (1931) and Spemann and
Schotte (1932) have described experiments in which, if ectoderm of species A is
grafted on to species B, this ectoderm is induced to form an organ characteristic
of species A and in the position on the host which corresponds to its normal
position in species A, although the host species B neither possesses that organ nor
any other in that position. The induction here can be more easily considered as
the specification of position co-ordinates than as a reaction to a stimulus whose
only function is to evocate the organ in question. It seems doubtful, however, if
one should conclude from this that "the reaction system can start a definite type
of development as a response to an unspecific stimulus" (Rotman, 1935), since
the type of development seems to be quite strictly determined by the position
co-ordinates, which are themselves definitely specified, that is, are fixed by some
agent which acts specifically at each point. This experiment brings up in an acute
form the question of what is the theoretical difference between individuation, the
specification of a whole system of points making up an I.F., and evocation, the mere
calling up of a new type of differentiation as we see it performed by a dead organiser
or a solution of a definite substance. It would seem that individuation can hardly
be anything other than a co-ordinated system of evocations, in which case we may
hope to isolate the various substances concerned in the specification of each point,
just as we are now isolating the substance which is common to the specifications
of all points within the neural plate.
In recent years several cases have been described in which the area of tissue
which can perform a given induction is considerably larger than the area which in
normal development actually does so. The experiments described in this paper
show that the classical induction of the neural plate belongs to the same type. The
areas which are capable of inducing have been spoken of {e.g. Holtfreter, 1933 a;
Spemann, 1934; Huxley and de Beer, 1934; Rotman, 1935) as "determination
fields". The use of the word "field" in this connection is unobjectionable if it
denotes some unit-building activity, but it appears sometimes to indicate merely
that the boundaries of the area are vague and perhaps that there is some variation
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in the strength of the inducing stimulus within it. Under abnormal conditions
the "field" may induce two or more organs instead of only one, so that it is clear
that in this usage no emphasis is being laid on any tendency of the field to form
a unit. Similar unanalysed usages of the "field concept" are so common in experimental embryological literature that it would be over-optimistic to expect them to
be given up, but it may be suggested that when one speaks of a field one should
be able to indicate either what is the end-product of the field activity, i.e. the field
should be defined by the equilibrium towards which it tends, as is done for I.F.,
or one should be able to name the field activity, e.g. one could speak of a diffusion
field of an evocator substance. Thus one could define a field by its tendency to
produce one complete induction, but hardly by its being an ill-defined area in
which an evocator substance is present. Such areas might be referred to by a more
neutral term such as "region" or "district".
VI. SUMMARY.
1. The just formed side-plate mesoderm from the gastrula in the medium-sized
yolk-plug stage can induce the formation of an extra neural plate when implanted
into the blastocoel of a young gastrula.
2. The dorsal lip of a young gastrula, substituted for the side-plate mesoderm
mentioned in (1), evocates a neural plate.
3. The failure of evocation by the side-plate mesoderm in normal development
can only be explained by supposing both that the evocating capacity of the sideplate mesoderm is lower than that of the dorsal lip and that the lateral ectoderm
does not react to an evocating stimulus as easily as does the young gastrula
ectoderm.
4. The weakness of the evocating capacity of the side-plate mesoderm might
be due either to its intrinsic nature or to an active suppression by the rest of the
mesoderm. The evidence suggests that both factors may be involved, but it can
be shown that the latter factor by itself is not sufficient to explain the facts.
5. Isolated gastrula ectoderm retains its competence to be evocated to neural
tissue at least until the age of an open neural plate embryo. Thus the normal loss
of competence by the lateral ectoderm is not due to an inherent process. Nor is it
caused solely by a continued connection with the neural plate. It cannot be due
merely to the presence of side-plate mesoderm; but it may be due to an influence
proceeding from side-plate mesoderm which is part of a mesoderm field, or it
may be dependent on a preparation of the ectoderm by reason of its connection
with the neural plate, or, more probably, by an inherent process, so that by the
stage at which the side-plate mesoderm forms, the ectoderm has become such that
it reacts with side-plate mesoderm with rapid loss of competence.
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