Sequence of Gene Action in Development | Animals | Embryology

When development starts the genes are in a repressed stage. During cleavage the genes are inactive (with the exception of histone genes), and whatever hereditary traits can be observed are due to gene action during the growth and maturation of the oocyte.

From gastrulation onward, some genes become activated, and the action of individual genes becomes evident. By observing normal development, it is usually not possible to state whether a particular advancement in the organization of the embryo is due to the action of a gene or genes.

In a mutant, however, one or more genes become different from the “normal” allele, or the arrangement of the genes in the chromosomes is changed (in translocations), and this change is made apparent by producing a deviation from the normal development of the organism.

Quite often the deviation is of the nature of a developmental arrest, and from this it may be inferred that the gene or genes in their normal, un-mutated state are somehow involved in producing the normal course of development.

If, therefore, we find that in a mutant some process leading to formation of organ rudiments is disturbed, we may conclude that this process is under the control of the normal allele of the mutated gene or is dependent on the normal arrangement of genes in the chromosomes.

Genes Affecting the Earliest Stages of Organogenesis:

There are several mutations in mice which produce a partial or complete duplication of the whole body. The duplication may be posterior, involving the tail, sacral, and hind-limb region, or more generalized (“kinky” homozygotes, symbol Ki).

The duplications could not have been produced later than the time of primary organ formation, possibly even during the gastrulation stage. The mechanism by which duplication is achieved is not known, but in this connection it is sufficient to know that the genetic constitution of the embryo may influence the morphogenetic processes involved in the formation of primary organ rudiments.

A mutant line is known in guinea pigs which show various degrees of abnormalities of the head. The abnormalities are of the nature of cyclopic defects; paired organs of the head tend to approximate each other on the ventral side and fuse into unpaired organs. In animals defective to a greater degree, the more anterior parts of the head disappear altogether, and even the entire head may be absent, while the organs of the trunk region are more or less normal.

These defects are so similar to cyclopic defects which can be produced in amphibians by removing the anterior part of the archenteron that it is hardly possible to doubt that in the mutant guinea pigs the origin of the abnormalities is a similar one. The abnormal genetic constitution in some way inhibits the action of the primary organizer (the chordomesoderm and the endoderm of the head region).

The external ear is also involved in abnormal guinea pigs, and this is a direct indication that the branchial region of the foregut developed abnormally, as the external ear is connected in its development with the first pharyngeal pouch, and its abnormal position could arise only if the arrangement of the pharyngeal pouches were defective right from the start. A similar mutation is known in mice, and it probably occurs in other animals as well.

Genes Affecting Organ Rudiments in Later Organogenesis:

An example of genetic control of organogenesis in a later stage is presented by Danforth’s short tail mutant in the mouse (symbol Sd). Externally, the mice carrying this gene differ from the normals by having a shortened tail or by the complete absence of the tail.

Another feature of interest is the reduction in size or complete absence of one or both kidneys found in these mice. The metanephros in mammals develops from two separate rudiments, the metanephrogenic tissue and the ureter, which sprouts from the mesonephric duct.

In Danforth’s short-tailed mice, the ureter buds off from the mesonephric duct as usual, but it tends to remain shorter and sometimes does not reach the metanephrogenic tissue at all. If the ureter does not reach the metanephrogenic tissue, the kidney does not develop, as induction from the ureter is necessary for the kidney tubules to be differentiated. If the ureter reaches the metaneph­rogenic tissue, at least a small kidney develops.

The size of the developing kidney depends on the degree of branching taking place at the end of the ureter, because only those parts of the metanephrogenic tissue which lie in the immediate vicinity of the tip of the ureter or its branches (the latter becoming the collecting tubules of the differentiated kidney) become differentiated into renal tubules.

Thus, the cause of the kidney defect is the arrest in development of the ureter as a result of the changed genetic composition of the affected animals. The arrest in development of the ureter prevents the establishment of the spatial relationship between inductor and reacting system (the ureter and the metanephrogenic tissue), which is necessary for the induction of the kidney to take place.

The genes responsible for excessive development may be represented by the genes causing an increase in the number of digits on the forelimb or hind-limb. Quite a number of such genes are found in different animals. The development of this condition has been studied in a mutation of the mouse called “luxate”. In these mice additional toes (one or two) appear on the pre-axial side of the foot, that is, on the inner side of the hallux. The anomaly can be traced back to the limb-bud stage, when the hind-limb-bud is excessively broad on its anterior edge.

In the next stage, when mesenchymal condensations appear, indicating the rudiments of the digits, the number of these condensations is greater than normal. As the size of each digit rudiment corresponds to the size in normal limbs, it seems plausible that the excessive number of digit rudiments is the result of the excessive amount of material provided for digit development in the abnormally broad limb-bud.

Effects of Genes on Growth:

Differences in size of animals are hereditary, but the control of growth and size is mostly determined by a multiplicity of genes. Occasionally, however, a single gene may have a marked effect on growth. The dwarf mutation in mice (pituitary dwarf, symbol dω) presents an example of this kind. The character is dependent on a single recessive gene. The homozygotic mice, which alone show the character, are born indistinguishable from normal individuals.

At the end of the first week of postembryonic life, however, the dwarf individuals begin to show a slightly retarded growth as compared with the controls. In the third week, the dwarfs are conspicuously smaller than normal, and after weaning they increase in weight only slightly.

The adult dwarfs are only one third to one fourth of the weight of normal mice. Retardation of growth in this case has been traced to an abnormality of the hypophysis, which is reduced in size and fails to produce the growth hormone.

This has been proved experimentally by transplanting pieces of fresh rat hypophysis subcutaneously into dwarf mice. The result was that the treated mice resumed growth and reached the size of normal individuals.

In this case, therefore, the gene does not directly affect the intrinsic growth rate or the cells’ ability to proliferate, but the primary effect of the gene is to modify in a certain way the differentiation of one of the organs (the anterior lobe of the hypophysis). The arrest of growth is then the visible expression of the deficiency of a growth-stimulating substance normally produced by the hypophysis.

Sequence of Gene Action and the “Biogenetic Law”:

The sequence of gene action in the course of development throws a new light on some generalizations which played a considerable role in embryology in the nineteenth century, namely, the “laws” of Baer and of Miller-Haeckel. Essentially, both “laws” stress the greater conservatism of the earlier stages of ontogenetic development rather than that of the later stages, as a result of which the earlier stages show features general to large groups of animals, while the more specialized features distinguishing lower taxonomical units become apparent during later stages. These features distinguishing closely related animals may be considered as later acquisitions in the course of evolution.

We have seen that mutations can affect all stages of ontogenetic development and that even the earliest stages may thus become changed. In spite of this, the cumulative effect of mutations must necessarily show a greater influence on the later than on the earlier stages. If a mutation occurs which changes any developmental process in an earlier stage, and if the embryo nevertheless remains viable, then a number of later pro­cesses might also be modified.

Mutations of genes which normally become activated during later stages of ontogenesis obviously cannot affect the earlier stages. In this way, the earlier stages of development would be modified by only a minority of mutant genes, while the great majority of the genes, both those acting in earlier stages and those acting later, would leave a mark on the later stages. The greater conservatism of the earlier stages can thus be given a rational genetic explanation.

It is obvious, however, that exceptions to the general rule are always possible. One obvious exception is presented by the structure of the egg. Lying, as it does, at the end of a life cycle (as well as at the beginning of a new one), the structure of the egg may be under the influence of genes becoming active throughout a lengthy period of life. It is, of course, well known that the structures of eggs, including egg membranes, show a great amount of variation. It is sufficient to point to the endless variety of sculpture found on the surface of insect eggs.