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Waddington CH. Principles of Embryology (1956) The MacMillan Co., New York

   Principles of Embryology (1956): Part 1 - 1 The Science of Embryology | 2 The Gametes | 3 Fertilisation | 4 Cleavage | 5 The Echinoderms | 6 Spirally Cleaving Eggs | 7 The Ascidians and Amphioxus | 8 The Insects | 9 The Vertebrates: The Amphibia and Birds | 10 The Epigenetics of the Embryonic Axis | 11 Embryo Formation in Other Groups of Vertebrates | 12 Organ Development in Vertebrates | 13 Growth | 14 Regeneration | 15 The Role of Genes in the Epigenetic System | 16 The Activation of Genes by the Cytoplasm | 17 The Synthesis of New Substances | 18 Plasmagenes | 19 The Differentiating System | 20 Individuation - The Formation of Pattern and Shape | References
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Chapter XV The Role of Genes in the Epigenetic System

The science of genetics has clearly shown that when an animal differs from nearly related forms, the nature of these differences is nearly always controlled by genes carried on its chromosomes. It is clear then that genes must be amongst the most important causal entities which play a role in guiding development. We have so far discussed the question of why an organ, such as a limb, develops as it does in terms such as organisers, fields, competence, etc. Genetics, following a quite different mode of analysis, formulates its answer to the same question in a quite different way. It finds that the development of the organ is dependent on the activities of certain genes in the fertilised egg. The task of this chapter is to present the picture of the development of an organ or tissue as seen in terms of genes. This will provide a view of the epigenetic system which we must take as being complementary to that derived from experimental embryology.

1. Developmental pathways and their genetic control

In using the data of genetics to throw light on the general character of developmental processes we are not concerned with the way in which any particular gene obtains its efftect—a question we shall take up in the next chapter. Here we want to start from the other end, taking an organ or tissue and seeing how genetics would lead us to envisage its development. It will be convenient before discussing particular cases to summarise the general principles which we shall in fact find to emerge. The most important of these are:

  1. The development of an organ or complex substance takes place in a series of steps, each of which is affected by genes.
  2. At each step there are several genes acting, and the actual development which occurs is the resultant of a balance between the opposing gene-instigated tendencies.
  3. At certain stages in the development of an organ, the system is in a more than usually unstable condition, and slight disturbances at such times may produce large effects on the later events. Such times have been called “epigenetic crises’.
  4. An organ or tissue is formed by a sequence of changes which can be called the “epigenetic path’ leading to it. In a normal egg which contains the genes usually found in the wild individuals of the species, these paths are rather definitely distinct from one another, so that a developing mass of tissue turns either into a leg or into a wing, say, but it is difficult to persuade it to become something intermediate. And also each path is ‘canalised’, or protected by threshold reactions, so that if the development is mildly disturbed it nevertheless tends to regulate back to the normal end-result (Waddington 19402).


As a first example in which these principles may be seen, we may consider the development of the wing in Drosophila (Goldschmidt, 1935), 1937, Waddington 1940b). The main features are shown in Fig. 15.1 in the form of somewhat diagrammatised drawings of the whole wing at various stages during its development in the pupa. In the larva at the time of puparium formation, the wing is a thickened area of the dorsal mesothoracic buds, an area which is already folded in towards the interior of the bud. Very shortly afterwards, the fold elongates and breaks through the thin opposite side of the bud (stage 2). The thick but pointed blade expands in area and becomes thinner, and as it does so, it becomes apparent that there are channels left open between the upper and lower surfaces; these are the pre-pupal veins (stage 3). Soon the wing, as well as expanding in area, becomes fatter by an inflation which forces the two surfaces apart, obliteratine the venation until the wing is transformed into a featureless sac (stage 4,The greatest swelling is reached just about the time of true pupation. From then onwards, the wing starts to contract again. As the two surfaces come together, they leave spaces between them: these are the adult veins, which appear first near the tip of the wing, and gradually spread back towards its root (stages 5, 6, 7). At first the tissue between the veins is spongy and loose in texture, but gradually it becomes more compact, the fluid which had filled the inflated wing sac being finally driven out to give an immature wing almost identical in outline with the final adult one, though smaller than it in size. In fact, after the last pupal stage drawn in the figure nothing much happens to change the morphology of the wing except the expansion of the cells, throwing the whole structure into folds which only become flattened out again after the imago emerges from the puparium.


FIGURE 15.1

The centre column shows eight stages in the development of the Drosophila wing during the pupal period, from the condition of an imaginal bud at the top, through the period of inflation to the adult condition. On the left are three gene-controlled modifications affecting wing shape: Xasta produces a distal nick as early as the imaginal bud stage; broad affects the direction of growth in the prepupal stage before the inflation; dumpy increases the longitudinal contraction after the inflation. On the right are three genes altering wing venation. Cubifus interruptus removes one of the prepupal viens. Net causes the appearance of extra venation, and veinlet the obliteration of the tips of the normal veins, during the contraction following the inflation. (Adult wings to smaller scale; after Waddington 1940b.)



The final wing is a simple-enough organ. It is practically two dimensional, since the thin upper and lower surfaces fuse tightly together; its outline is a simple oval slightly indented where the most posterior vein cuts it; and the whole system of venation consists only of one vein forming the fore-edge and four main longitudinal ones radiating from the base of the wing with two short cross-veins between them.


The wing path of development is affected by very many genes; Waddington (1940b) has described the abnormalities produced by some thirty of them, and a fair number of others are known. The mutant alleles of these genes are recessive to the wild-type alleles; that is to say, the epigenetic path is canalised to the extent that an alteration of only one of the two alleles to the mutant form does not suffice to produce any noticeable alteration in the course of development, presumably because some thresho!d is not exceeded in the heterozygote.


A few of the recessive forms are illustrated in Fig. 15.1, which shows how their development diverges from the normal pathway. Each step in the normal sequence is influenced by genes, which often act upon the developing tissues in opposite directions. For instance, in the prepupal wing, the relative rates of cell division in different directions are affected by the genes broad, expanded, lanceolate and narrow, of which the first two cause the wing to become broader and the last two longer. Again, the time of the pupal contraction is a minor epigenctic crisis, during which the contracting wing is in a state of delicate balance, influenced by genes such as dumpy, lumpy and spade, which tend to increase the contraction in length, blade which tends to increase it in width, balloon and bloated which tend to reduce the contraction in general; while genes whose primary effects are to change the shape of the wing margin may produce secondary effects at this time, since if the wing is abnormally long and narrow, or short and broad, before the contraction starts, these characteristics will become exaggerated. During the later stages of the contraction, the imaginal veins appear as cavities remaining between the two wing epithclia and there are some genes, such as veinlet, tilt, radius incompletus, which tend to cause obliteration of veins, while others, such as plexus or net, work in the opposite sense, and produce extra veins.


From a study of this large number of genes affecting the development of a single organ, a picture of the gencral epigenetic situation emerges. Direct investigation by more conventional experimental techniques has confirmed it in many points. Thus Lees (1941) made defects in the developing wing by pricking it with a needle at various definite times, and could interpret his results in terms of the same sequence of developmental mechanisms as the genetic study had revealed. Goldschmidt (19352) Henke (1947), Schatz (1951) and others have treated Drosophila pupae with just sub-lethal temperatures at definite times, and found that a series of abnormalities of wing development occur which parallel in a striking manner the forms produced by mutant genes. Such abnormalities which are similar to the phenotypes characterising genetic races but which are produced by environmental stimuli, are known as ‘phenocopies’. Henke found the interesting fact that the time at which a temperature shock was capable of causing the appearance of a phenocopy of some particular mutant type was usually near to, or just before, the time at which the development of that type first diverges visible from the normal. For instance, shocks just before or during the contraction phase tend to produce dumpy- or blade-like phenocopies. For each type of phenocopy there is a ‘sensitive period’ during which it can be relatively easily induced* (Fig. 15.2).


The fact that the sensitive period for the phenocopy of a gene occurs very near the time at which the development of the mutant becomes recognisably abnormal suggests at first sight that this is the stage of development at which the gene becomes active. It is, however, by no means clear just what might be meant by ‘the time of action of a gene’. If an embryo contains a certain mutant gene, that gene is present in its cells from the time of fertilisation onwards. Long before there is any visible abnormality of development, the gene may have been producing some unusual substance which is merely stored up within the cell without being detectable by existing methods. The fact that an external agent can produce a given phenocopy most easily at a certain stage of development is a sign that the relevant epigenetic process is most unstable at that time. It is not surprising that it should be just at this time that the mutant gene also begins to produce detectable divergences from the normal course of development, but this does not tell us whether the gene has been active earlier or not. Nor, of course, are we justified in concluding that the gene acts by a mechanism similar to that of the environmental stimulus; in fact during a sensitive period many different external stimuli (heat, cold, x-rays, etc.) may produce similar effects, and it is clearly impossible that all of them can be disturbing the system in the same way that the gene does. Phenocopy studies can thus provide some information about the stability of the epigenetic situation in the developing tissues, and can reveal the ‘point of attack’ of a gene, but can as a rule tell us little about the gene’s mode of operation or the time of its primary activity.

  • 1 Occasionally there are two different sensitive periods, for instance when very similar end-results can be brought about in two different ways.


The sensitivity of a stock of animals to environmental stimuli is under genetic control. One can, by selection over a number of generations, build up strains whose hereditary constitution predisposes them to respond in particular ways to any given treatments. This specification of the developmental stability of the organism is surprisingly precise and detailed; it usually depends, in any given case, on rather a large number of genes; and starting from any fairly large population, it seems to be always possible to find in it genes which will confer on their bearer almost any type of developmental reactivity one chooses. These facts again bring to our attention very forcibly the complexity of the genetic system which controls developmental processes. (For discussion of the evolutionary implications of phenocopy-formation and similar phenomena, see Waddington 1953), 19540.)



FIGURE 15.2

The curves above show the frequencies per cent of various types of phenocopies produced when a temperature shock (3-5 hrs. at 39° C.) was given at certain times after puparium-formation to a stock of D. melanogaster. The type of wings corresponding to the various curves are shown below, together with the wild type(+). They are: (a) first broadened type; (6) dumpy type; (c) first narrowed type; (d) rounded end type; (e) second broadened type, usually curved as well;(f) normal proportioned but small; (g) second . narrowed type. (From Schatz 1951.)



We may now turn to another example of a developmental sequence which has been well analysed from a genetical point of view (Lees and Waddington 1942, Lees and Picken 1945). The formation of the bristles (macrochaetae) in Drosophila appears, by histological investigation, to be an extremely simple process, directly involving only two cells per bristle (Fig. 15.3). In the pupae of about fifteen hours’ age slightly enlarged cells may be found in the hypodermis. Already they are sometimes in pairs, though they may also occur singly. By nineteen hours they are always paired, and it is probable that a division, producing a pair of cells, occurs in the period from about twelve to eighteen hours. The two cells proceed to grow rapidly, attaining a volume about a thousand times as great as that of the neighbouring hypodermal cells. During this process the nuclei enlarge greatly, and the chromosomes assume the polytenic banded form which is best developed in the salivary gland cells. The pair of cells become arranged in a characteristic way, with one lying above and slightly to one side of the other. The upper cell, which is known as the tormogen, is destined to form a more or less circular socket of hardened chitinous material, while the lower one, the trichogen, produces a long gradually tapering bristle which sticks up through the centre of the socket. A whole series of genes affects this relatively simple sequence of processes. In the first place there are some, such as scute, which cause an absence of certain of the normal bristle cells, and others, such as hairy, which produce extra pairs; nothing further is known about their mode of action. The next stage, that of the cell division to produce the trichogen-tormogen pair, is affected by split, which often provokes an extra division to give a group of four cells; these become somewhat irregularly arranged, and may give rise to two trichogens and two tormogens or only one of the former and three of the latter. Another gene, dichaete, has a somewhat similar action, but it is usually only the tormogen which divides a second time and becomes doubled. In the next step, the precise arrangement of the tormogen above and to one side of the trichogen is also under genetic control. In hairless, shaven-naked and prickly, both cells lie side by side at the surface and both produce sockets, so that no hair is formed; while in stubble the tormogen is shifted slightly to one side and sits less firmly on the trichogen, and the hair is thicker and shorter than normal. These phenomena indicate that the shape of the bristle is at least partly due to the moulding of the still-fluid secretion of the trichogen as it is forced through the constricting ring of the tormogen. Several genes affect the nature of this secretion and the rate of its production. Spineless and morula reduce its amount considerably, so that only short and thin bristles are formed, and the secretion of the trichogen is also reduced to the level characteristic of the tormogen in those mutants in which both cells lie side by side at the surface (hairless, shaven-naked, prickly). In stubble the early rate of production is increased but the final value is much the same as in normal animals. Some other genes have a more subtle effect. During its secretion the bristle seems to consist of a thin plastic wall and a more fluid core, the whole of which eventually hardens and becomes hollow. The wall is probably formed of an oriented long-chain high-polymer in a rubber-like state, almost devoid of cross-linkages between the chains. It normally grows just at the rate required to provide enough surface to accommodate the fluid secretion which is being forced into it by the trichogen. This delicate balance between growth in surface and in volume is disturbed by certain mutant genes. In singed and forked the volume may suddenly increase too fast (or the surface too slowly) so that the bristle ‘explodes’ and forms bulges and kinks, while in bristle there are gradual and periodic changes in the volume surface/relationship, so that a series of fairly gentle swellings arises. Moreover these genes also effect the mechanical properties of the surface, which is more plastic in singed and forked and more elastic in bristle.


  • 1 There are one or more other pairs of cells closely associated with these; a general description is given by Henke (1953).


FIGURE 15.3

The genetic control of bristle development in Drosophila. A and B are sections through the thoracic hypodermis of the mid-pupa, showing two stages in the development of the bristle-forming (trichogen, frch) and socketforming (tormogen, for) cells. C, surface view. D, surface view showing the extra division which occurs in split, giving (E) duplicated bristles. I, surface view, and G, section, in Hairless, when the trichogen and tormogen lie side by side at the same level, and give two sockets (H). In shaven-naked (I, J,) the situation is similar but usually not so extreme. In Stubble (K, L, M) the tormogen does not embrace the trichogen as closely as usual, and an abnormal thick bristle is produced. N shows the irregular bristles produced by forked. (From Lees and Waddington 1942.)


Many of these mutant types of bristle may also be produced in phenocopies, but the correlation between the sensitive periods and the points of attack of the genes is not so fully worked out as for the wings.

An even more impressive demonstration of the real complexity of apparently simple developmental processes is provided by the chemical investigations which have been made in recent years on the eye pigments of Drosophila (Beadle 1945, Ephrussi 1942, Nolte 1952) and various other insects, e.g. the meal worm Ephestia (Kiihn 1941, Caspari 1949) and the silkworm Bombyx (Kikkawa 1953). In Drosophila at least twenty-five genes are known to affect the colour of the eyes, which normally are a slightly brownish red. Analysis of the effects produced when two different mutant genes are both present in homozygous condition led to the suggestion that there are two main pigments, a brown and a red, and these were later found to be separately extractable with suitable solvents. They are both of relatively low molecular weight, though probably bound to proteins when they are in the natural state in the living cell.

Rather little is known about the development of the red pigment, except that it fails altogether in the absence of the normal allele of brown (bw*) and is affected less profoundly by many different genes. Chromatographic analysis has quite recently shown that it is in fact really a mixture of a rather large number (about ten) of different components (Heymann, Chan and Clancy 1950) and that certain other fluorescent components are closely associated with it (Hadorn 19514, Hadorn and Mitchell 1951).

The production of the brown pigment provides a good example of a sequence of developmental steps, and is particularly interesting because it has been possible to discover the actual chemical changes involved in some of these. Sturtevant (1932) pointed out that in a fly heterozygous for vermilion (v/v+) it can sometimes happen that the vt chromosome gets lost at a mitosis, and that a patch of cells with the constitution v may appear among the heterozygous eye facets, which are normal in colour. When this happens with most other genes, an abnormally coloured group of cells can be clearly seen, but no departure from the normal wild-type pigmentation is found in patches which can be shown, on other evidence, to be v in constitution. Sturtevant therefore suggested that some substance diffuses into these cells from the surrounding tissue and compensates for the absence of the v* gene.

Beadle and Ephrussi developed a technique of transplanting pupal eyediscs into the body-cavity of other larvae, and by suitably choosing the genotype of the host and of the transplant, were able to show that there are at least two diffusable substances (which they rather unhappily called ‘hormones’) concerned in the production of the brown pigment. One of these is produced under the influence of the normal vermillion gene (v*) and is lacking if that gene is replaced by the mutant-vermillion allele (v), while the other is similarly related to the cinnabar gene. Investigation finally showed that these substances are derived from tryptophane, which is converted first (under the action of y+) into a-oxytryptophane, which is then oxidised (by a reaction for which no separate genetic control has been identified) to kynurenine, which was before its identification known as the vtsubstance. This in its turn is converted, under the influence of the cn* gene into a ‘cn* substance’, which is probably 3-hydroxy kynurenine; and after this two further steps of reaction, controlled by the normalcardinal and normal-scarlet genes, intervene before the actual brown pigment is formed (Fig. 15.4).


The reactions leading to the brown pigment must be linked in some way with those leading to the red, since some genes, particularly those of the white locus, affect them both. Probably this gene is essential in connection with some common substrate or carrier-protein, which has to link up with the cn+ substance and with something equivalent in the reaction-series leading to the red pigment. It is interesting to note that the c+ substance can only produce its effect during a certain limited period of development, extending from sometime after puparium formation for about fortyeight hours. Presumably before that time the kynurenine is not yet available, while by the end of the period of sensitivity it must have been converted into something else. This provides a clear parallel to the restriction of periods of competence found in more usual experimental embryological studies. It is also worth pointing out that phenocopies of eye-colour mutations cannot be easily produced by environmental shocks of a general nature, such as high or low temperatures; the epigenetic system is not complex enough to be unstable with respect to such non-specific agents.



FIGURE 15.4 Eye pigment development in Drosophila. (After Beadle 1945.)


Another well-analysed system of pigmentation is that of the guineapig hair colour (Wright 1942). It will not be described here but it well illustrates the point which is being made, namely the real complexity of apparently simple developmental processes.


There is a further important point about developmental paths, or sequences of epigenetic reactions, which has not been adequately illustrated by the examples so far described. That is the existence of sharp distinctions between the comparatively small number of alternative paths which normally occur in the development of a particular species. In embryological studies, we have seen (p. 179) how amphibian gastrula ectoderm is competent to become cither epidermis or neural tissue or mesoderm, and in the great majority of cases becomes quite definitely either one or other of them. A similar situation is revealed by some genes in Drosophila. For instance, Goldschmidt (1938, 1945) has shown that in flics of certain abnormal genotypes, what would normally be the presumptive wing tissue enters on one of the alternative epigenetic paths, and develops as a haltere; or in another genotype it becomes a leg. If the normal aristopedia gene is replaced by its mutant allele (ss‘), the tuft on the antenna known as the arista may develop into the terminal section of a leg, with perfectly developed claws.

Genes which produce this type of effect, in which a part of the embryo develops into an organ which is normally located somewhere else in the body, are known as homeotic genes. A considerable number of them are known in Drosophila. Besides aristopedia, for instance, proboscipedia converts the mouth parts into a leg-like organ; tetraltera converts the wings into halteres, while tetraptera converts the halteres into wings; podoptera causes the wings to become legs, while bithorax changes the whole metathorax into a mesothorax. Some of these effects can also be produced by environmental agencies; thus Gloor (1947) found that cther treatment of the young larva a few hours after laying would produce a phenocopy of bithorax, presumably by changing the condition of the larval hypodermis at the time when the imaginal buds are first being formed. Similar changes can, however, also be produced at a much later stage since, as we saw (p. 141), abnormalities in the folding of the imaginal buds just before pupation may cause parts of them to develop into tissues which should belong to another part of the body. It is probable then that most of the homeotic genes act in the first place at the time imaginal buds are first formed but that these alterations do not produce any definitive effect until about the time of pupation.

Once a piece of tissue has entered on a path of development, its final condition can be affected by all the genes which are concerned in that path. Thus, if, in an animal in which the arista takes the leg path owing to the presence of the mutant ss* gene, the genes concerned with the development of the leg have been replaced by mutants such as fourjointed which produce shortened legs, then the aristal leg will also be shortened; while THE ROLE OF GENES IN THE EPIGENETIC SYSTEM 341

genes which usually affect the arista will now have no effect on it (Waddington 1940c). This shows that, as might be expected, the activity of a gene is not determined simply by the geographical location within the body, but by the type of developmental process which is going on (Fig. 15.5).


FIGURE 15.5

The mutant allele ss** in Drosophila converts the whole arista into a leg, while the allele ss*¥ changes only the proximal part into a leg, the distal part remaining an arista. A gene th (thread) which normally removes the branches from the arista, affects only the arista-like portion in ss flies, and fj (four-jointed) which shortens the legs also shortens the leg-like arista of ss°°. (From Waddington 1940a.)

Primary arid secondary effects of genes

Some of the studies we have mentioned, particularly that of Beadle and Ephrussi on the eye colour genes, were at one time thought to hold out the hope of leading us to an understanding of the primary, immediate effect of a single gene. This has turned out, so far, to be illusory. It has in no case proved possible to be absolutely sure that the gene-effect we can see is the primary one. The subject is discussed more fully later (p. 379), but it is important at this stage to consider some general points about the kinds of primary and secondary effects which genes may have on the development of organs and tissues.


During the development of a complex animal, any alteration produced by a gene at an early stage may have many later repercussions, perhaps in quite other organs than that in which the original effect occurred. A very obvious case is that in which a gene affects an organ of internal secretion. For instance in the mouse a certain gene impairs the secretion of the growth hormone by the pituitary, and, as might be expected, this affects all these structures for which the hormone is important, so that the animal develops as a dwarf.

Griineberg (1948) has shown that many other cases in which a gene has manifold and widespread effects can be explained in a similar way. One of the best-known examples is that of a certain lethal in rats. Animals homozygous for the gene show a very diversified complex of symptoms, which eventually lead to their death at an early age. Griineberg (1938) argues that all (or nearly all) the symptoms can be plausibly considered to be secondary consequences of an original hypertrophy of the cartilage. The network of causation which he postulates in this case is shown in Fig. 15.6. Falconer, Fraser and King (1951) have described another case, in which a gene ‘crinkled’ in mice produces a large number of different effects which they suggest can be almost entirely accounted for as the results of a suppression of hair follicle formation between twelve and a half and seventeen days of gestation and after birth. The suggestion that all the effects in this case are actually secondary consequences of one initial abnormality receives very strong support from the fact that another different gene tabby also produces (in single dose) exactly the same syndrome. If cach symptom was brought about by a separate reaction of the gene, such a parallelism could not be expected unless the crinkled and tabby genes were identical, which the genetical evidence shows them not to be; whereas if there is one single underlying cause for the syndrome, it is easy to imagine that two or more different genes may affect the basic process and thus produce the same complex end-result.

Hadorn (19484, 1950, 1951) has paid particular attention to the “pattern of manifestation’ of a gene, i.e. the particular collection of organs whose development it alters. He studied certain ‘lethals’ in Drosophila, that is genes whose effects are so profound that individuals homozygous for them do not survive. He emphasises, first, that there are critical periods of development at which death tends to occur. Thus many lethals are known which produce death at the end of the embryonic period, and again there are many for which the time of death is at puparium formation, or at emergence; but there are very few which kill during the middle of larval life. These sensitive periods are the times when a great deal is going on in the epigenetic system, so that slight abnormalities in the tissues, which may have been produced considerably earlier, will then cause drastic effects. They have also been referred to as “epigenetic crises’, and are of various grades of severity.

Hadorn went on to show that if the phenotypes produced by the lethal genes are closely examined, each gene will be found to cause a characteristic pattern of damage, exhibited either by the death and


‘Anomaly of cartilage’’

Narrowed lumen of Thickened ribs Slight changes in larynx trachea and nose

Fixation of thorax in inspiration

bce

> Kyphosis Abnormal! situs of Spur on deltoid ridge of <> thoracic viscera humerus

Emphysema Bronchicctasis


Slow suffocation Increased resistance General arrest Blocked nostrils in pulmonary of development circulation

y

Coma exposure Compensatory Blunt snout _ Inability to suckle inanition hypertrophy of right ventricle of heart Decompen- Capillary Faulty occlusion Starvation sation haemorrhages of incisors into lungs

Difficulties in feeding

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Exitus Exitus Exitus Exitus - Exitus



FIGURE 15.6 A gene in the rat causes abnormalities in the formation of cartilage. This has many secondary consequences (‘pleiotropic effects’). (After Grueneberg 1938.)


degeneration of the cells of particular tissues, or, when the effect is weaker, by a retardation of growth. This pattern differs in detail in different stocks of the lethal, depending on the other genes associated with it (the ‘genetic background’). More important from the present point of view is the fact that the pattern in which the gene normally manifests itself is a mixture of primary and secondary effects. That is to say, in some tissues the abnormality is a direct consequence of the activity of the lethal gene in those particular cells (a primary effect), while in other tissues the gene may either be inactive, or ineffective because its action fails to surpass some threshold, yet the tissue may develop abnormally because it is influenced by unusual substances produced elsewhere in the body (a secondary effect). Hadorn demonstrated the reality of such secondary effects by showing that certain organs from larvae of a lethal type will continue to develop more or less normally if transplanted into host larvae of a wild-type strain. For instance, lethal-meander and lethal-translucida both die usually at about the time of puparium formation; but the imaginal buds, if transplanted into normal hosts, can carry through a complete metamorphosis. Their death when left undisturbed is therefore a secondary consequence of abnormalities in the development of other parts of the body (probably the protein-metabolising system in the gut of lethalmeander and some other nutritive or hormonal peculiarity in lethaltranslucida).

The distinction between primary and secondary effects can of course also be made within the confines of a single organ. For instance, if the primary effect of a gene is to cause the absence of large parts of the anterior and posterior regions of the wing (e.g. Beadex or Lyra) a secondary consequence is that when the pupal contraction occurs the longitudinal veins become squeezed nearer together and diverge at a smaller angle (Waddington 1940b).) The fact that in Hadorn’s cases the secondary effects occur in different organs to the primary ones is not the essential point of the distinction, but merely makes it easier to recognise which effect is nearer the very first influence of the gene on the sequence of developmental processes.

“Hadorn has provided a diagram, reproduced in Fig. 15.7, which expresses neatly some of the ways in which secondary effects may occur. In this, the rectangles 1, 1 and mi represent three cells in three different organs, as it might be Imaginal Bud, Fat Body and an Endocrine Gland. In each cell ten genes are represented. It is supposed that in each type of cell the heavily ringed genes are active, producing substances (large rings) which fit together into a reaction-chain. Consider what would happen if various of these genes mutated. If the activity of 8 was altered, nothing would be changed except in organ 1, where a primary manifestation would occur. If 3 mutated, that would cause a primary effect in 1m and a secondary one in I, in the reaction-chain of which an essential link is a product of m1, the ‘hormone’ b. If, before the lack of b had had irreversible consequences, organ I were transplanted into another host with unmutated 3, then supplies of b would be available to it and it would develop normally. Again, mutations in 4, § and 6 would cause secondary effects in 1 and m as well as a primary one in 0. But if a mutation occurred in genes I or 2 or 10, both organs 1 and m would be altered, and these alterations would both be primary ones.



FIGURE 15.7

Diagram of a sequence of gene reactions in three different tissues. See text. (From Hadorn 1950.)


When a gene affects several different organs or tissues it is said to be ‘pleiotropic’. The term is not always a very precise one, since in borderline cases there may be difficulty in deciding whether two effects are to be considered the same or different (c.g. in Beadex or Lyra above). The concept has, however, been widely discussed, since it clearly is of great importance to discover whether any one gene can only exert one type of immediate effect, or whether a single gene can do different things. It is clear there is no evidence for more than one type of gene-action in cases where the whole of a complex pattern of manifestation can be shown to consist of a set of secondary consequences of some single primary effect (as in the mutation of 3 above, or Griineberg’s rat lethal described on p. 342). Griineberg speaks of this as ‘spurious pleiotropy’, contrasting it with ‘genuine pleiotropy’, in which the same gene would be doing different things in different tissues. The difficulty with this latter category, however, is that at present we have no certain way of detecting it. We can discover cases which seem to be of the type produced by a mutation of gene J, i.e. in which there are two or more apparently primary effects which are not influenced by other tissues. But there is no way of telling whether the mutated gene 1 is doing the same thing in organ I as it is in organ 1m, and we can at best class this as an ‘apparently genuine pleiotropy’.

Most attention, from the embryological side, has recently been given to cases of spurious pleiotropy, since the secondary effects may reveal some of the epigenetic interrelations between tissues.

The primary effects, however, are also not without interest. In a case of ‘apparently genuine pleiotropy’ we are confronted with two or more at first sight disconnected developmental processes, which are shown actually to be related by the fact that one particular gene is involved in all of them. They must therefore have some fundamental similarities; and the nature of these offers a very important problem which may go to the very heart of the epigenetic systems involved. To take an example. In Drosophila, split causes both an extra division in the bristle-forming cells (followed by various abnormalities in their arrangement), and also an effect on the facet-forming cells of the eye which is in the main a deficiency in the normal number of cell divisions (accompanied also by some irregularity in arrangement). Now the facet-effect of split is almost exactly mimicked by morula, another effect of which is to reduce the growth rate of the bristle-producing cells so that the chaetae are smaller than normal. This bristle-effect of morula, in turn, is mimicked by spineless; and many of the alleles at the spineless locus cause as well the ‘aristopedia’ phenotype, characterised by the conversion of the arista into a leg, the basic alteration being perhaps one on the growth rate and folding of the imaginal bud, We have then a series of developmental reactions, revealed by the mutant phenotypes of split, morula, and aristopedia, which would seem quite disconnected from one another were it not that the overlapping pleiotropies show that there are some basic relationships at the level of apparently primary gene action (Lees and Waddington 1942, Waddington and Pilkington 1943).


Genes may also be used in another way to reveal basic relationships between developmental processes, namely by breeding animals which simultaneously show the effects of the two genes which one wishes to compare. For example, it has been mentioned that in hairless and shavennaked some of the trichogens and tormogens are shifted so as to lie side by side, while in stubble there is slighter effect in the same sense in all the cellgroups. Now in hairless-shaven flies the effect is very strongly exaggerated, and occurs in nearly every group, while in stubble-hairless or stubble-shaven there is a straightforward summation of the two effects. From this one may conclude that the actions of hairless and shaven belong to one group and those of stubble to another. One cannot be certain of the nature of the relationships within and between groups, but it has been suggested that genes which show exaggeration when combined are those ee act at the same time on the same epigenetic process (Shomodynamic’ genes), while with those which act at different times the buffering of the system reduces the severity of the effects (Waddington 1953).

Suggested Reading

Beadle 1945, Ephrussi 1942, Goldschmidt 1938, pp. 3-98, Hadorn 19484, 1950, Griineberg 1948, Waddington 1940b, 19484, Weiss 1947, 1950b, Wright 1941 or 1942.



   Principles of Embryology (1956): Part 1 - 1 The Science of Embryology | 2 The Gametes | 3 Fertilisation | 4 Cleavage | 5 The Echinoderms | 6 Spirally Cleaving Eggs | 7 The Ascidians and Amphioxus | 8 The Insects | 9 The Vertebrates: The Amphibia and Birds | 10 The Epigenetics of the Embryonic Axis | 11 Embryo Formation in Other Groups of Vertebrates | 12 Organ Development in Vertebrates | 13 Growth | 14 Regeneration | 15 The Role of Genes in the Epigenetic System | 16 The Activation of Genes by the Cytoplasm | 17 The Synthesis of New Substances | 18 Plasmagenes | 19 The Differentiating System | 20 Individuation - The Formation of Pattern and Shape | References
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