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The mouse has been the subject of numerous studies of the effects of genes on development. All of the work prior to 1951 has been thoroughly reviewed by Grüneberg ( 1952), and his later book ( Grüneberg, 1963) is a review of developmental studies on genes affecting the skeleton. Other chapters in this book deal with the effects of genes on the development of pigment ( Chapter 21), blood ( Chapter 17), metabolic and endocrine disorders (Chapters 19, 20, and behavior (Chapters 32, 33). In this chapter I shall not try to describe in any detail the results of studies on the effects of individual genes on development of the mouse. I shall rather try to summarize the kinds of contributions to understanding of development that have been made by these studies. It will be clear immediately that these investigations have raised more questions than they have answered.
There are two main reasons for studying the developmental effects of mutant genes in an animal like the mouse. One is to discover the causes of pathological development of conditions similar to inherited human diseases in the hope of devising cures and preventative measures. The other is to discover how genes control development by investigating how mutant genes change normal development. Studies on the mouse may be expected to contribute to both of these purposes since the mouse is subject to a number of known hereditary diseases similar to those of man, with many others probably yet to be discovered, and since the genetic constitution of the mouse is better known and more easily manipulated than that of any other mammal.
BIOCHEMICAL MUTANTS
In seeking answers to the general question of how genes control development, the first step is to frame more specific questions. In multicellular organisms many kinds of cells are formed and it is clear that although each kind contains the whole array of genes present in the zygote, only certain genes are active in each different kind of cell. In some way genes are called into action at particular times and promote changes which may then call certain other genes into action or repress the activity of others already active. Probably the important basic questions for the field of developmental questions are: What determines when a particular gene will act, and what does it do when it does act?
The ultimate answers to these questions will have to be in biochemical terms. A start has been made toward answering them in work with inducible enzymes in bacteria, organisms without cellular differentiation but with various gene-controlled functions inducible by environmental changes. The important principles discovered in this work have been set forth by Jacob and Monod ( 1961). In bacteria there are "structural" genes which carry the information determining the structure of certain enzymes made by the cell and transmit the information to the cell by way of messenger ribonucleic acid. In addition, there are specific regulatory loci controlling the production of repressor substances which, by interaction with environmental factors, determine whether or not a particular structural gene will become active. The interaction between environmental factors and the products of regulatory loci are relatively simple in bacteria. In higher organisms the controlling mechanisms are undoubtedly enormously more complicated and may involve chains of interactions between many genes. For some suggested schemes see Monod and Jacob ( 1961). Evidence is accumulating that many hormones produce their effects by "turning on" the process by which genes make proteins ( Williams-Ashman, 1964) but it is not yet known why only certain genes in certain cells respond. There is evidence that the histones, proteins which are usually bound in some degree with the DNA of chromosomes, may act as repressors of gene action and play a role in the response of genes to hormonal stimulation as well as to other kinds of activation ( Bonner and Ts'o, 1964). Elucidation of the details of these processes would constitute a large part of the answer to the question of how genes control development.
In the mouse a number of loci are known to determine variations in amount or kind of protein. By definition those controlling changes in amino acid composition of the protein chain are regarded as structural loci. Such differences have been demonstrated directly only for the hemoglobin loci ( Hba and Hbb, Chapter 17) but are inferred for other loci on the basis of electrophoretic or physical differences. Some other such loci are the albino ( c, Chapter 21) and β-glucuronidase ( g, Chapter 19) loci, and probably also the transferrin ( Trf), serum esterase-1 ( Es-1), salivary amylase ( Amy-1), pancreatic amylase ( Amy-2), erythrocytic esterase-1 ( Ee-a), isocitrate dehydrogenase ( Id-1), and immunoglobin (Ig-1, Ig-2) loci ( Chapter 8). Other loci may be either structural or regulatory: serum esterase-2 ( Es-2), kidney esterases ( Es-3, Es-4), erythrocytic esterase-2 ( Ee-2), and prealbumin component ( Pre) ( Chapter 8), which determines presence or absence of electrophoretically demonstrated proteins; hemolytic complement ( Hc, Chapter 8) which determines the presence or absence of complement activity; and levulinate dehydratase ( Lv, Chapter 19), and liver catalase ( Ce, Chapter 8), which determine high and low levels of an enzyme. Pyrimidine degrading ( Pd, Chapter 19) may be a regulatory locus of some kind, since it appears to govern the activity of three enzymes simultaneously.
Since these genes are concerned with proteins, the primary product (after messenger RNA) of the genes, the activity by which these loci are recognized is probably fairly close to the primary gene action. For the albino locus, for example, it is probable that the primary product of the locus is tyrosinase. It is also reasonably certain that tyrosinase is formed in the melanosomes of the melanocyte and produces melanin there ( Moyer, 1963). At least part of the question, "What does the c locus do?" is thus answered, but nothing at all is known about what causes the c locus to go into action at this particular place. Most and probably all of the genes mentioned in the preceding paragraph are active in only one or, at most, a few kinds of cells and have no detectable activity in other cells. There is at present no clue as to the nature of this difference between cells or how such a difference is brought about.
MORPHOLOGICAL MUTANTS
Leaving the still largely unexplored area of gene action at the primary biochemical level in the mouse, we now consider what can be learned from a study of the more remote effects of genes, principally at the physiological or morphological level. The morphological mutants can be classified in many different ways, but for convenience they will be considered here under two headings which are not necessarily mutually exclusive: mutants providing natural experiments and pleiotropic mutants.
Natural experiments
To study the mechanisms of differentiation and morphogenesis and the interrelationships of various developmental processes, embryologists perform experiments which change the conditions at a particular stage and observe the consequences in later stages. Mammalian embryos are not easily accessible to the embryologist, and, although many ingenious experimental procedures have been devised for dealing with them, it is still difficult to interfere mechanically with a mouse embryo in its normal uterine environment without destroying that environment. Mutant genes can often serve the same purpose as the embryologist's experiment by interfering with a developmental process and allowing the later consequences to be observed under natural conditions. Some restraint is usually necessary, however, in interpreting the causative relationship in a sequence of gene effects, since it is not always certain whether a late effect of a mutant gene is the result of a particular earlier effect or an effect of the mutant acting through some other pathway. A few cases of natural experiments are described below.
The effect of alleles at the W locus ( Chapter 17) has been used to settle an old dispute on the origin of the primary germ cells ( Mintz and Russell, 1957). The gonads of W/ W mice at birth are very deficient in germ cells. By an alkaline phosphatase staining technique which selectively stains primordial germ cells, Mintz and Russell showed that stained cells were present in the yolk sac of normal embryos at 8 days of gestation. Between 8 and 12 days they increased in number and moved along the wall of the hindgut to the germinal ridges. In W/ W embryos the stained cells were present in normal numbers at 8 days, but this number increased very little between then and 12 days. The deficiency of migrating cells in embryos known to be defective in capacity to produce germ cells is very strong evidence for the extragonadal origin of the germ cells.
The apical ectodermal ridge of the limb buds has been shown to play an important role in the outgrowth of the limb buds ( Saunders, 1948; Zwilling, 1956). The sequence of events in the development of the limbs of mice with syndactylism ( sm/ sm, Chapter 8) offers further evidence for the importance of the apical ectodermal ridge. The third and fourth digits of affected mice are fused. Grüneberg ( 1960) has shown that the first detectable effect of sm in homozygotes is a patchy, localized hyperplasia of the epidermis of the limb buds and tail accompanied by hyperplasia of the apical ectodermal ridge of the limbs. The footplates subsequently become enlarged and concave ventrally, presumably as a result of overgrowth caused by excess stimulation by the enlarged apical ectodermal ridge. The abnormal shape of the footplates pushes the developing digits together with resulting syndactyly.
Bateman ( 1954) used the mutant grey-lethal ( gl, Chapter 8) to study the normal pattern of bone growth. The gene causes retardation of accretion and lack of erosion of bone. By comparing the size and shape of bones or normal mice with those of their mutant sibs at 3 weeks of age, Bateman was able to show the exact sites of both accretion and erosion in the growth of normal bone.
It is known from the results of experiments with amphibians and birds that differentiation of the otic vesicle into a normal ear is dependent on the inductive influence of the neural tube. Two mutants of the mouse, kreisler ( kr) and dreher ( dr), provide evidence supporting this relationship for mammals (Deol, 1964a, 1964b). In kreisler, segmentation of the rhombencephalon and its associated neural crest is abnormal, so that the otic vesicle is prevented by intervening ganglion cells from coming into contact with the neural tube. Subsequent development of the labyrinth is abnormal and similar to that obtained in experiments with amphibia in which the relationship between neural tube and otic capsule is moderately disturbed ( Deol, 1964a). Dreher mice also have an abnormally formed labyrinth, but the abnormality is not so severe as in kreisler. Deol ( 1964b) suspected that the neural tube might be abnormal in these mice also. His investigation confirmed this suspicion and showed that the abnormality of the neural tube precedes that of the otic vesicle by at least one day.
Mice bearing the mutant dominant hemimelia ( Dh) lack a spleen, have a small stomach, short intestine, an abnormal urogenital system, preaxial polydactyly or oligodactyly of the hind feet, and tibial hemimelia ( Searle, 1964). At 9 days of gestation, before any of these structures are present, the splanchnic mesoderm of the anterior and posterior parts of the coelom is abnormal in mutant embryos, more so in Dh/ Dh than in Dh/+. At this stage normal splanchnic mesoderm has an epithelial-like structure which is less evident or absent in the mutants (M.C. Green, unpublished data). The occurrence of defective mesoderm at this early stage suggests that normal organization of the splanchnic mesoderm is necessary for normal development of the spleen, stomach, intestine, urogenital system, and hind limbs. By analogy with the known inductive effects of the epithelium of the apical ectodermal ridge of the limb bud, it can be postulated that the effect of the splanchnic mesoderm may be dependent on its epithelial-like structure and may be inductive in nature.
Pleiotropic mutants
Many mutants of the mouse are pleiotropic; that is, they have two or more apparently unrelated effects. Mutants of this kind provide evidence for developmental relationships that might not be revealed in any other way. The evidence is especially convincing if there is more than one locus with the same array of effects. Multiple effects of a mutant at a single locus may conceivably be due to the "mutant" being in fact a small deficiency affecting several loci. The occurrence of two or more independent loci with the same array of effects virtually rules out this explanation. Some examples of such cases are discussed at length in other chapters; here I will only mention them and draw attention to a few other cases.
An outstanding example of pleiotropism in the mouse is the multiple effect of mutants at the W and Sl loci ( Chapter 17). Both loci affect development of erythrocytes, pigment cells, and germ cells. It has not been possible, in spite of a large amount of work by many investigators, to discover a common basis for the three defects, but the existence of these two loci, as recognized by their mutant alleles, makes it almost certain that the three types of affected cells, or their precursors, have some common gene-controlled property. This property must be specific to these cells and not shared by other kinds of cells.
Recessive mutants at two different loci (piebald, s, and lethal spotting, ls) both cause irregular white spotting, and both also cause megacolon in some or all of the animals homozygous for each mutant. The megacolon is associated with a deficiency of intrinsic ganglion cells in the rectum and lower part of the colon ( Bielschowsky and Schofield, 1962; Lane, 1966).
It has long been a question among students of pigmentation whether white spotting is due to a defect in pigment cells themselves or to an inhospitable environment in the skin which prevents pigment cells from becoming established there ( Markert and Silvers, 1956; Chapter 21). Ganglion cells and pigment cells are both known to be derived from neural crest. The simultaneous deficiency of pigment cells and ganglion cells in mutants at two loci makes it very likely that the defect in both cases is in the neural crest and that the spotting in these cases is indeed due to defective pigment cells. Experiments by Mayer and Maltby ( 1964) and Mayer ( 1965) on the development of pigment cells in ls/ ls and s/ s mice have added evidence in support of this hypothesis (Chapters 8, 21).
The circling mutants, of which there are nearly 20, are characterized by a tendency to run in circles, head-tossing, hyperactivity, and in many cases deafness (Chapters 8, 32). All have defective labyrinths, the vestibular part only being defective in those not deaf, the cochlea also in those deaf. Most of these mice cannot orient themselves properly when submerged in water and may have difficulty finding their way to the surface. The deafness is easily explained by the abnormalities of the cochlea; the inability to orient themselves is explained by abnormalities of the semicircular canals, sacculus, and utriculus. The circling, head-tossing, and hyperactivity, however, are not obvious consequences of the observed pathological conditions. Their nearly universal association with abnormalities of the vestibular labyrinth suggests a close causative connection. A further interesting point in this case is the very large number of independent mutations with similar effects on behavior. At first glance the number seems inordinately large. However, the labyrinth is a complicated structure and many genes must contribute to its development. The striking symptoms and the fact that the abnormalities are quite compatible with life allow mutations at any of these loci to be easily detected. In contrast, mutations affecting the eye, for example, may be quite numerous but are not so easily detected.
A number of mutant genes causing pre- or postaxial abnormalities of the limbs are known. Most of them are listed in Table 15-1 which gives their effects on the limbs as well as on variation in number of presacral vertebrae and ribs (see Chapter 8 for more complete descriptions). Five of the 11 mutant genes affect the number of the ribs or presacral vertebrae or both. Of the remaining six, two are known not to affect the number of presacral vertebrae, and four have apparently not been observed for thus character. It should also be mentioned here that differences in number of ribs and presacral vertebrae are commonly observed between inbred strains (Green, 1951, 1954, 1962; Searle, 1954; McLaren and Michie, 1954, 1955), and are also a further effect of several mutant genes which cause short or kinked tails ( Ts, dm, tk, sc, ur, vt, and T; Chapter 8). Carter ( 1954) has proposed a theory to explain the relationship of hind limb abnormalities and vertebral shifts in the case of lx. The theory supposes that the limb is formed by the interaction of an inductor, presumably resident in the ectoderm, with an underlying competent tissue, presumably the mesoderm. A forward shift of the inductor would place it out of line with the competent tissue and result in a limb that is deformed and displaced forward. The forward displacement would result in a forward shift of the pelvic girdle and therefore fewer presacral vertebrae. Under this scheme a backward shift of the competent tissue could be invoked to explain the abnormalities produced by lu ( Forsthoefel, 1959). This scheme is almost certainly wrong in detail (see Zwilling and Ames, 1958; Forsthoefel, 1959; and Grüneberg, 1963, p. 235-237 for more detailed discussion), but it can surely be no coincidence that abnormal hind limbs are so frequently associated with a change in the anteroposterior position of the pelvic girdle.
During the ninth day of embryonic life in the mouse the hind limb begins to form. It forms at the level of the posterior end of the coelom. Prior to this time the coelom and tail gut extend nearly to the end of the tail bud. During the ninth day the tail bud and the tail gut grow rapidly and soon leave the coelom far behind. At about the same time segmentation, which has been proceeding along the midgut region, arrives at the hind limb level and the end of the coelom. Closure of the nerve cord takes place at the hind limb level at about this time also. It seems possible that variation in the timing of these various events might well produce variation in the position of the limb bud and hence of the pelvic girdle. Some variations might be compatible with normal limb formation and others not. These relationships have not been investigated. To do so by means of experimental procedures may be very difficult in mammals. Mutants which cause changes in limb level with and without limb abnormalities, as well as inbred strains with differences in limb level, provide the natural experiments by which these relationships may be investigated.
A further generalization can be made from the facts in Table 15-1. Preaxial limb defects tend to be confined to, or more severe in, the hind limbs; postaxial limb defects are more severe in the forelimbs. It seems worthwhile to draw attention to this correlation, even though no explanation is apparent. There seems to be no relationship between the direction of the vertebral shift and the pre- or postaxial nature of the limb defect.
Not included in Table 15-1 are other limb mutants which cause syndactyly ( Os, sm, sy), fusion of bones of the forearm and shank ( ld) or shortening of the limbs ( bp, sho). These mutants tend to affect both fore and hind limbs, though not always equally, and no effect on number of ribs or presacral vertebrae has been reported for any of them.
SEX-LINKED MUTANTS
This chapter would not be complete without the mention of the special features associated with the action of sex-linked genes in development. Several lines of evidence led Lyon ( 1961) to propose the hypothesis that in female mice, and perhaps in other female mammals as well, one of the two X chromosomes is inactivated early in embryonic development. Either the maternal or the paternal X can be the one inactivated, but once the decision has been made, all cells descended from a particular cell have the same inactivated X. Evidence in favor of this hypothesis is as follows.
In many kinds of cells of female mice and other mammals, one chromosome of the proper size to be considered an X chromosome is heteropycnotic ( Ohno and Hauschka, 1960; Tjio and Östergren, 1958; Chapter 7). The heteropycnotic chromosome is probably the one inactivated. The Barr body seen in the interphase nuclei of females of many species of mammals is probably the heteropycnotic X. (See McKusick, 1962, for summary of the evidence and for references.)
The Lyon hypothesis predicts that for sex-linked genes with localized gene action (as, for example, genes determining the color of pigment cells) heterozygous females will be mosaics. This is in fact the case in the mouse. All known sex-linked coat color mutants in the mouse cause a mosaic or mottled phenotype with patches of normal and mutant color in heterozygous females. This is true of Mo, Mobr, To, Modp, and Blo (Chapters 8, 21). The sex-linked mutants, tabby ( Ta) and striated ( Str), which affect hair structure, also have mosaic coats with transverse stripes of normal hair interspersed with stripes of hair of abnormal structure ( Lyon, 1963). In addition, females heterozygous of translocations between the X chromosome and an autosome bearing a color mutant, with the wild-type allele on the translocated chromosome and the mutant allele on the normal chromosome, have a variegated phenotype with patches of normal and mutant fur ( Russell and Bangham, 1961; Cattanach, 1961).
When the phenotype produced by sex-linked genes is not due to localized gene action, the genes may appear either semidominant or recessive, depending on the mode of gene action and the number of normal cells necessary to insure a normal phenotype. Thus, jimpy ( jp), a lethal mutant which causes abnormal behavior and severe defects of myelination of the central nervous system ( Sidman et al., 1964), is usually completely recessive in its effects on behavior, but Phillips ( 1954) has reported one presumably heterozygous female showing the abnormal behavior. Lyon ( 1961) suggests that this individual may represent and example of the rare instance when by chance all the cells responsible for the jimpy trait had the normal gene inactivated. The mutant bent-tail (Bn), on the other hand, has an intermediate effect in heterozygotes and fails to manifest itself in a proportion of them, suggesting that the effect may be proportional to the number of determining cells in which the mutant allele is active.
Mice with an X/O chromosome constitution are known to exist and to be normal viable fertile females ( Welshons and Russell, 1959). This shows that only one X chromosome is necessary for normal development. The two X chromosomes in normal females appear to do no more than the single X of normal males, judging by the similarity of effect of sex-linked mutants in homozygous females and hemizygous males. A Ta/ Ta female is no more severely affected than a Ta/Y male. Nothing is known about the specific proteins controlled by any sex-linked loci in mice, but in man there is no difference between males (X/Y) and females (X/X) in the level of several substances controlled by specific normal sex-linked alleles, for example, glucose 6-phosphate dehydrogenase and antihemophiliac globulin ( McKusick, 1962). The Lyon hypothesis offers a ready explanation for this phenomenon of "dosage compensation."
Translocations between the X and the autosomes involving linkage groups I and VIII produce variegated phenotypes in mice heterozygous for the translocation and bearing a color mutant on the intact chromosome ( Russell and Bangham, 1961; Cattanach, 1961; Russell, 1963). Russell ( 1963) has mapped the autosomal break point for a number of these translocations and has shown that the amount of variegation of the autosomal coat color mutants is different in the different translocations and not necessarily related to the closeness of the locus to the break. The results are consistent with the hypothesis that the capacity to inactivate translocated autosomes is not evenly distributed along the X. Mapping of the X-chromosome break points of these translocations should reveal the distribution of the inactivating capacity on the X.
If the Lyon hypothesis is indeed true, the tissue in which a sex-linked gene is active should be a mosaic or normal and abnormal cells in females heterozygous for the mutant allele of that gene. If the abnormality is recognizable in individual cells by some means, one may thus be able to identify the tissue in which the gene has its effect. Thus females heterozygous for jimpy ( jp/+) might be expected to show patchy defects of myelination in the central nervous system if the jp locus is active in myelin-producing cells. If myelin is found to be completely normal in heterozygous females, the site of gene action is probably elsewhere. The site of action of autosomal loci may be studied in the same way if suitable translocations can be obtained between the X chromosome and the autosome bearing the locus. For example, one such translocation ( Cattanach, 1961) has a piece of the chromosome bearing the wild-type allele of albino ( c) in linkage group I transposed to the X chromosome. A mutant at the closely linked locus shaker-1 ( sh-1) causes degeneration of parts of the membranous labyrinth. It is not known whether the sh-1 locus is included in the translocated piece, but if it is, in females of the appropriate genotype carrying the translocation, the degeneration should be patchy if the site of gene action is in the degenerating cells themselves. This method of investigating gene action has not been explored in the mouse.
Russell et al. ( 1964) have used X-autosome translocations to investigate certain other properties of genes. If the autosomal loci translocated to the X chromosome are inactivated in approximately half of the cells, mice can be obtained that are mosaic for patches of cells hemizygous and homozygous for a mutant allele. For recessive color mutants, comparison of the two types of tissue may show whether the mutant is completely inactive or not. By this method, pink-eyed dilution ( p) was shown to have some activity, since p/0 cells appear as light mottling on a p/ p background. Brown ( b) has no activity, since b/0 is indistinguishable from b/ b. The same system was used to determine whether lethal mutants at these loci were cell-lethal. Most were found not to be cell-lethal.
SUMMARY
Studies of the effects of genes on development in the mouse may be expected to contribute to knowledge of how genes control differentiation. Although the explanations will ultimately have to be in biochemical terms, very little is known about the primary biochemical action of most mutants in the mouse.
Some examples are given of mutants which produce altered proteins. It is not yet known how the action of these loci is controlled.
Mutants may sometimes serve the same purpose as embryologists' experiments by interfering with a developmental process and allowing the later consequences to be observed. Mutants with two or more apparently unrelated effects (pleiotropic mutants) may provide evidence for developmental relationships not otherwise easily detectable. Examples of both of these kinds of mutants are briefly described with a more extended discussion of pleiotropic mutants affecting the limbs and axial skeleton.
The inactive X-chromosome hypothesis provides an explanation for the frequent mosaicism of females heterozygous for sex-linked mutants, and for "dosage compensation" in the action of sex-linked genes in males and females. It also provides a new approach to the analysis of developmental effects of sex-linked genes and of genes made effectively sex-linked by X-autosome translocations.
1The writing of this chapter was supported in part by research grants G15826 and G18485 from the National Science Foundation.
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See also
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Science 144: 309-311.
See also
MGI.
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See also
MGI.
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See also
PubMed.
Zwilling, E., and J.F. Ames. 1958. Polydactyly, related defects and axial shifts — a critique. Amer. Natur. 92: 257-266.
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