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While Mocha's effect on pigmentation and behavior is difficult to reconcile, there is some evidence that a subtle relationship between pigmentation and the trace element, manganese, may be responsible for the effect which pallid ( pa) has on behavior (Erway et al., 1966, 1971).
Pallid, an autosomal recessive (chromosome 2), was described originally by E. Roberts ( 1931) after a mouse displaying the mutation was caught in the country and brought to his laboratory at Urbana, Illinois in 1926. According to Roberts "the eyes were pink, indistinguishable from the eyes of the common pink-eyed varieties, but the coat color, though plainly agouti, was lighter than that of a pink-eyed black agouti." Because the phenotypic effects of pallid ( Plate 2-H) are similar to those of pink-eyed dilution, it has sometimes been referred to in the literature as "Roberts' pink-eye" or "pink-eye-2" ( p2) ( Grüneberg, 1952).
Pallid dilutes yellow pigment as well as black and brown. Yellows homozygous for the mutation ( Ay/a;pa/pa) are a light lemon color and animals homozygous for both pallid and pink-eyed ( pa/pa;p/p) have very light-colored coats, significantly lighter than those produced by either of the genes separately ( E. Roberts and Quisenberry, 1935; Grüneberg, 1952).
Because pallid mice have pink eyes, when combined with viable dominant spotting ( Wv/Wv; which ordinarily produces a black-eyed white animal) a "mock-albino" phenotype results ( Erway et al., 1971). However, it should be stressed that whereas albinos have amelanotic melanocytes (see Chapter 3, Section II, A), Wv/Wv;pa/pa mice do not (see Chapter 10, Section I, D).
Theriault and Hurley ( 1970) have compared the occurrence and ultrastructure of developing melanosomes in the retinal epithelium, the sensory epithelium of the inner ear, and the epidermis of pallid ( a/a;pa/pa) mice with those of C57BL/10 ( a/a) animals (see also Hearing et al., 1973). They found that in 14-day-old a/a embryos there were melanosomes in all stages of development in the retinal epithelium and pigment granules were present in the utricular epithelium, whereas in pa/pa embryos no melanosomes occurred in the inner ear and only premelanosomes were present in the retinal epithelium. Uniformly dense melanosomes resembling a/a mature melanosomes also were not observed in 1- and 3-day-old pallid retinas and in 15-day-old and adult samples there was a conspicuous absence of melanosomes in any developmental stage, although pigment granules were found in the choroid layer of the eye 7 The inner ear epithelium of young pa/pa mice also lacked both mature and immature melanosomes. On the other hand, melanosomes in different stages of development were present in the cytoplasm of pallid epidermal melanocytes at 6 days postpartum. These granules, however, never became completely electron dense and their melanin was deposited in a coarsely granular way, without any coalescence. Moreover, not all of the granules were evenly electron dense, and similar differences occurred even within a single granule. Pallid granules in epidermal melanocytes were smaller than a/a;B/B granules, spherical, and never larger than 0.5 microns ( Theriault and Hurley, 1970). 8
In addition to its effect on pigmentation, Castle ( 1941) observed that when maintained under crowded conditions the viability of pallid mice was considerably reduced and that they "tended to be nervous and jumpy." 9 These behavioral defects were subsequently shown by Lyon ( 1951) to be associated with otolith defects within the inner ear. She noticed that some pallid animals displayed defects in their postural reflexes which were of two main types. The first type was noticeable when they were 2 — 3 days old and held up by the tail. Whereas a normal mouse reacts by flexing its spine and neck dorsally while stretching its forelimbs forward, pallid mice sometimes "flexed the spine and neck ventrally and stretched the limbs backward, i.e., they failed to respond normally to change of position" ( Lyon, 1953). The second type of postural defect noticed by Lyon developed during the third week of life when some pallid animals, which hitherto seemed normal, displayed "an asymmetrical posture and walked about with the head constantly tilted to one side" ( Lyon, 1953). Still other pallid mice displayed none of these abnormalities and remained normal.
Lyon was able to demonstrate that the anatomical basis of these postural and behavioral defects could be traced to the absence of one or more otoliths ( Lyon, 1951). A normal mouse has two otoliths, one in the sacculus and one in the utriculus. "Those pallid mice which failed to respond to position change always lacked both otoliths from both ears and those with a normal response always possessed at least one otolith. Animals with asymmetrical posture showed asymmetry of the otolith defect, and tilted the affected side of the head upwards. Those with completely normal otoliths had normal behavior" ( Lyon, 1953). 10
It thus appears that whereas pallid always alters eye and coat color, its effects on the otoliths show incomplete penetrance and variable expression. To account for this variability Lyon carried out a number of experiments and demonstrated that both the genetic background upon which pallid acted, as well as environmental factors, contributed to its penetrance. She found that the proportion of pallid mice which lacked otoliths was higher in brown pallid ( b/b;pa/pa) mice than in nonbrown pallids. Whether this is due to and effect of b itself or to some closely linked factor(s), and whether it is related to the fact that both pa and b are coat-color determinants is, of course, impossible to say.
Lyon ( 1953) observed also that the effect which pallid had on the otoliths was related both to litter size and litter order. Increasing litter size produced an increase in penetrance, especially in young and old mothers, i.e., small litters from females at their reproductive prime were least affected. Moreover, in an elegantly conceived experiment she was able to show that this effect of litter size was due to the number of fetuses surviving after implantation and not to the number of ova shed or the number implanted ( Lyon, 1954). She postulated that the otolith defect "may be due to competition (in utero) for food substances, either general or particular, or for oxygen, space, etc." ( Lyon, 1954).
While these studies made it clear that the behavioral defects of pallid mice were due to abnormal otolith development and helped focus attention on some of the factors which contributed to the expression of this abnormality, they failed to explain how this effect might be tied in with the influence pallid had on pigmentation. The idea that perhaps such an association was related to a deficiency in manganese stemmed from a series of experiments by Hurley and her associates ( Hurley et al., 1958; Hurley and Everson, 1963). These studies demonstrated that if pregnant normal animals are maintained on a manganese-deficient diet, a phenocopy of the pallid otolith defect occurs. They also showed that if pregnant pallid mice are given high concentrations of this trace metal at the appropriate time, 11 their offspring behave normally and display normal or almost normal otolith development (Erway et al., 1966, 1970, 1971). Although these treatments had no effect on pigmentation Erway and his associates ( 1966, 1971) propose that since the abnormality of the otoliths in pallid mice can be remedied by treating with manganese, and as melanocytes have not been found in the inner ear of these mice (see above), that the manganese requirement of this mutant is abnormal, and that the melanocytes act as a local reservoir of this trace element (see Cotzias et al., 1964; Van Woert et al., 1965). They suggest "that certain pigment mutations (such as pa) may produce subtle effects on trace-element metabolism, which in turn may alter the delicate balance of enzyme systems requiring these metallic co-factors. In the case of pa, the evidence indicates that the synthesis of mucopolysaccharides, comprising the matrix in which otoconia are formed, is affected" ( Erway et al., 1970). They believe that this hypothesis not only helps explain some of the pleiotropic effects associated with coat-color determinants, but accounts for why melanocytes accumulate in certain regions of the body such as the labyrinth, harderian gland, substantia nigra, etc. ( Erway et al., 1971).
To clarify the relationship between pallid's effect on pigment and otolith development, Erway and his colleagues ( 1971) determined the influence that albinism ( c) and viable dominant spotting ( Wv) had when combined with pa/pa. They reasoned that inasmuch as c presumably disrupts tyrosinase activity, it should suppress "the effect of pa on otolith development if pa exerted its effect on manganese availability via an alteration of the melanin substructure (e.g., greater chelating capacity for manganese)." Similarly, they thought that inasmuch as Wv/Wv removes all melanocytes from the coat it might "be expected to suppress the effects of pa on otolith development if the removal of melanocytes from other regions of the body did not withdraw manganese from circulation." Because neither of these genes affected the expression of pallid on otolith development, it was concluded that pallid influences manganese metabolism not through melanin per se but via some earlier effect, presumably on the melanosomes, and that "albino animals, presumably containing amelanotic melanocytes in the inner ear, also possess the manganese reservoir." they contend also that the inability of Wv/Wv to abrogate the influence of pallid on otolith development suggests that pa produces a very highly localized state of manganese deficiency, a conclusion in accord with biochemical and ultrastructural comparisons of liver mitochondria from manganese-deficient and pallid mice ( Hurley et al., 1970).
While this hypothesis relating the behavioral effects of pallid with its influence on pigmentation is an intriguing one, it nevertheless remains to be confirmed (see Deol, 1970b; Lane and Deol, 1974) (see also Chapter 6, note 11).
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