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1 ln occurred spontaneously in a highly inbred chocolate ( a/a;b/b) stock.
2Because Castle and his associates ( 1936) found that d/d mice were heavier than their nondilute littermates, Castle ( 1940) concluded that d also affects body size. In the light of a more carefully controlled analysis by L. Butler ( 1954), however, it seems more likely that this influence is due to linkage, i.e., close to the d-locus there are genes which affect body size.
3dl occurred as a spontaneous mutation in the C57BL/Gr strain ( Searle, 1952).
4Kelton and Raunch ( 1962) compared the development of myelination in the brain and rostral portion of the spinal cord in D/D, D/dl and dl/dl animals, beginning at 4 days of age, and observed no differences. However, when the brains and spinal cords of these same genotypes were examined for the presence of degenerating myelin, as revealed by the Marchi method, the vestibulospinal, spinocerebeller, and tectospinal systems of the dl/dl animals, but not of the others, displayed signs of degeneration. With few exceptions, this degeneration occurred within 1 or 2 days of the onset of myelinization.
5Coleman ( 1960) reported that the enzyme, phenylalanine hydroxylase, which converts phenylalanine to tyrosine, had only 50% of normal activity in DBA/1J ( a/a;b/b;d/d) mice and only 14% of normal activity in mice homozygous for dl. Coleman did not attribute this decreased activity to a direct effect of the d-locus on the production of the enzyme but rather to an inhibitor he found in the particulate fraction of liver homogenates. His results also indicate that more than one gene was involved in decreasing the activity of the enzyme in DBA/1J animals. Thus, coisogenic D/D mice had 86% and genetically unrelated dilute black ( a/a;d/d) mice had 65 to 75% of normal phenylalanine hydroxylase activity. These findings, along with the fact that the dilute black mice were not as susceptible as DBA/1J animals to audiogenic seizures, raised the possibility that these seizures were somehow related to the enzyme deficiency (see S. Huff and R. Huff, 1962; S. Huff and Fuller, 1964). Rauch and Yost ( 1963) reported that dilute lethal mice could neither transaminate nor hydroxylate phenylalanine as well as normal mice and that these defects were most pronounced during possible critical periods of postnatal development. Accordingly they suggested "that reduced enzyme activities lead to elevation in serum phenylalanine level which may in turn be responsible for those behavioral abnormalities that are related to myelin degeneration in the brain." On the other hand, Mauer and Sideman ( 1967) found that dl/dl mice displayed no difference from their normal littermates in levels of serum phenylalanine. Assays of liver phenylalanine hydroxylase activity, based on radioactive tracer methods, also failed to reveal any defect in this aspect of phenylalanine metabolism. Zannoni et al. ( 1966), too, did not find any evidence that phenylalanine hydroxylase activity was reduced in dl/dl mice. They likewise did not find any elevation in the concentration of phenylalanine in the blood or of phenylpyruvic acid in the urine of these animals (see also Woolf, 1963). Dilute-lethal has also been reported to influence both the total amount and the rate of increase of adrenal epinephrine and norepinephrine levels. Thus, according to Doolittle and Raunch ( 1965), by 3 weeks after birth dl/dl mice have about 25% more epinephrine and over twice as much norepinephrine as do normal mice.
6 ds was recovered from a (C57BL/6J x DBA/2J)F1 litter, and the d15 mutation was radiation induced.
7According to R.J.S. Phillips ( 1962), d15 homozygotes are easily distinguishable from d/d and at about 20 days of age develop characteristic behavior abnormalities similar to those which occur in dl/dl mice (the larger the animal the earlier the symptoms develop). If weaned, d15 homozygotes usually die between 3 and 4 weeks of age. If, however, they are given wet mash, many live for a considerable time. At least one male has lived long enough to breed.
8A considerable number of d-locus mutations have also occurred in the course of radiation experiments at Oak Ridge ( L. Russell, 1971). These include (1) 10 viable mutations (known as dx), all of which produce a somewhat darker phenotype than d/d when homozygous; (2) 3 mutations which are apparent repeats of d; (3) 14 mutations which when homozygous are lethal prenatally (known as dpl); and (4) 95 mutations which in two doses are lethal postnatally (known as dop). This last class of mutants do not differ among themselves in any easily recognizable way, nor do they differ from dl. All are phenotypically indistinguishable from d/d, produce clonic convulsions with opisthotonus and are lethal before weaning age.
9The difference between Ay/a;D/d and Ay/a;D/D does not occur in a/a animals and is most pronounced on the ventrum, which appears almost white in Ay/a;D/d. Microscopic examination of Ay/a;D/d hairs show no clumping of granules but a general reduction in their numbers along the entire shaft. This reduction is most pronounced in the ventral hairs where there may be a complete or almost complete absence of granules. This semidominant expression of d is also observed on the belly of at/at;D/d mice (and presumably would be discernable in Aw/Aw animals as well) which have a black dorsum and a very pale yellow ventrum. It does not occur in recessive yellow ( e/e) mice. Thus, in contrast to the situation in lethal yellow mice, e/e;D/D and e/e;D/d genotypes are indistinguishable (Poole and Silvers, unpublished).
10There is one mouse strain, known as the PET (for Pigmented Extraepidermal Tissues) strain, which displays an exceptionally wide disposition of melanocytes in the connective tissues of the body. This strain, which has been studied in detail by Reams and his associates ( Nichols and Reams, 1960; Mayer and Reams, 1962; Reams, 1963, 1966, 1967; Rovee and Reams, 1964; Reams and Schaeffer, 1968; Reams et al., 1968, 1976) was derived from an accidental cross between C3H mice and black mice of unknown origin obtained from a local pet shop in Richmond, Virginia. A survey of these mice made shortly after the strain was established showed that, although the distribution of melanocytes was not consistent from animal to animal, within the strain as a whole they occurred in almost every tissue of the body, including cartilage, bone, serosae, and many other tissues (lungs, heart, gonads, etc.). In fact, melanocytes were consistently absent only from the connective tissues of the gut mucosa ( Nichols and Reams, 1960). As time passed and a number of PET sublines were produced, it became apparent that each of them could be characterized by the particular localization of melanocytes within various tissues or body regions. Unfortunately, however, all but one of these lines, one in which the melanocytes are restricted to the skin and to certain muscles of the hind limbs, are extinct ( Reams, 1963).
11Because melanin pigmentation of the skin involves the production of melanosomes by melanocytes and their distribution to malpighian cells, and because the latter may play an active role in controlling the rate of synthesis of melanosomes, these two cell types can be looked upon as comprising a structural as well as a functional unit. Accordingly, the term epidermal melanin unit has been coined ( Fitzpatrick and Breathnach, 1963; Hadley and Quevedo, 1966; Quevedo, 1972). One might loosely define this unit "as a melanocyte with an associated pool of malpighian cells, the number of which may be variable" ( Fitzpatrick et al., 1967). In this view, factors which influence any component in the "epidermal melanin unit" might be expected to alter the function of the entire system. Thus, the effect which UV has in stimulating melanogenesis may not be due to its direct effect on melanocytes, but rather to its ability to induce the proliferation of malpighian cells thereby providing more vehicles for melanin transport ( Fitzpatrick and Breathnach, 1963). Genetic mechanisms, such as d/d and ln/ln, also obviously influence the size of the "epidermal melanin units" by restricting the number of dendritic processes. Also "epidermal melanin units" may overlap with two or more melanocytes sharing some malpighian cells in common ( Hadley and Quevedo, 1966).
12Following exposure to UV the epidermal melanocytes of d/d hairy and plantar skin are, in general, less dendritic than those of D/D skin but often possess more numerous and better developed dendritic processes than the pigment cells in unirradiated plantar d/d skin ( Quevedo and J. Smith, 1963; Quevedo and McTague, 1963). To account for this, Quevedo and McTague raise the possibility that UV treatments may "increase the permeability of the cellular interstices of the epidermis for penetration by the dendrites of melanocytes." They also deem it conceivable that an increase in melanogenesis results "in the filling of pre-existing amelanotic processes with pigment granules, thus rendering them visible."
13 p is linked with the albino ( c) locus (recombination 16% in females, 12% in males) ( M.C. Green, 1966a). This linkage was the first to be reported in any vertebrate ( Haldane et al., 1915).
14According to Carter et al. ( 1958), the coats of A/—;pd/p mice are rather like A/—;b/b. pd/pd mice are not as dilute as pr/pr ( Searle, 1968a) or misty ( m/m) (see Chapter 5, Section VI).
15As pointed out by L. Russell ( 1964), if the mottling were the result of a somatically mutable wild type allele, then mottled (plus, perhaps, fully wild type) progeny should not exceed 25% in these matings.
16The heavily mottled animals usually are gonadal mosaics. Eye colors in these mottled mice range from pink to full color, and often show bilateral asymmetry ( Wolfe and Coleman, 1966). Indeed, because reversion to + are so readily distinguishable in the cleared retinal pigment epithelium of pun/pun, Searle ( 1977) suggests that such pink-eyed mutants can provide a means of studying somatic reversion induced by chemical agents (see Chapter 12, note 32).
17The somatic reversion rate varied from 1.8 to 5.8 x 10-4 depending on the mating involved.
18Preliminary results from matings designed to test the role of meiotic recombination in the parental effect on reversion of the pun allele indicate that reversion frequencies are significantly higher in pun/pun progeny of +/pun female x pun/pun male matings, where recombination at the p-locus in the female parent is uninhibited, than in matings where recombination is inhibited or prevented by the presence of a translocation ( Melvold, 1972).
19The effects which various p-alleles have on the reproductive system have received a considerable amount of attention. The p6H, p25H, and pbs alleles when homozygous cause sterility in males and semifertility in females, whereas pd/pd, pun/pun, and p/p animals have normal fertility. Pituitaries from sterile males have significantly lower proportions of gonadotropic cells than pituitaries from fertile males. Pituitary gonadotropins appear likewise to be reduced in these sterile genotypes, although the lesion cannot be localized ( Melvold, 1974). The ovaries of semifertile females contain large numbers of developing follicles, but no corpora lutea or corpora hemorrhagica have been found. Semifertile females also have high numbers of polyovular follicles ( Melvold, 1974). According to Wolfe ( 1967, 1971) p/p and pun/pun (nonmottled) females release more ova than P/— females when inoculated with pregnant mare serum and human chorionic gonadotropins, an enhanced response which has been traced in part to the greater endogenous gonadotropic activity of their plasma and pituitary. These females also have larger ovaries and uteri, and seem to have a shorter ovarian cycle than P/— females. Similar differences in reproductive function also appear to exist for males which have significantly larger seminal vesicles (but not preputial glands or testes) than P/— males. The evidence, based on bioassays, indicates that there is an increased synthesis and release of gonadotropin by p/p (and pun/pun pituitaries, but neurohumoral release mechanisms of the hypothalmus, such as luteotropin releasing factor, cannot yet be excluded. How this effect which p has on hormone secretion relates to its influence on pigment remains to be determined (if such a relationship exists). According to Wolfe ( 1971), the only possible connection would seem to be that due to the inability of pink-eyed animals to form pigment there is "an accumulation of gonadotropin precursors or a change in regulatory control in favor of gonadotropin synthesis." In this regard, it would be of interest to know whether any correlation exists between the gonadotropic activity of pun/pun and pun/p genotypes and their degree of mottling.
20Hearing and his associates ( 1973) found that melanogenesis in ru/ru mice is also delayed in the choroid until after birth. They also observed a decrease in the melanization of each granule and a subsequent reorganization of fibrillar melanosomes into particulate melanin granules, especially in the choroid.
21Hearing et al. ( 1973) note that since tyrosine levels are reduced in ru/ru and p/p mice, one must consider the possibility that one or more forms of this enzyme are inactivated as a result of these mutations.
22A mutation which appears to be a repeat of ru-2 (called ru-2r) occurred at Oak Ridge in the C57BL/10 strain. Although mice homozygous for this mutation may have slightly lighter eyes at birth than ru-2/ru-2 animals, this difference is probably due to genetic background ( Kelly, 1974).
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