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In considering the influence of grey-lethal on pigmentation, one is faced with the dilemma of whether to limit the discussion to those operations which bear directly on this subject or to include the considerably greater number of efforts which have been directed toward investigating the other effects of this osteopetrotic mutant. the decision to include a brief resume of all of the effects of this mutation is based on the belief that they are germane and that such treatment may help focus attention on the mutation's primary effect.
Grey-lethal [ gl; chromosome 10 ( Lane, 1971)], which is fully recessive, was first described by Grüneberg in 1935 (see also Grüneberg, 1936a, 1938). It occurred as a spontaneous mutation in a stock segregating for ce and was recognized by the fact that on a wild type background it appears to remove most, if not all, of the yellow pigment from the fur; the coat is a slate grey color instead of the brownish hue of the normal agouti mouse. The gene has no effect on eumelanin synthesis but can be recognized in the presence of nonagouti by its influence on the phaeomelanin-containing hairs round the ears, genital papilla, and mammae. Grey-lethal yellow mice ( Ay/—;gl/gl) can best be described as khaki-colored.
Although originally it was believed that grey-lethal removed all of the yellow pigment from the fur ( Grüneberg, 1935) this, of course, is not the case. Microscopic examination of either the yellow region of A/A;gl/gl hairs, or of Ay/—;gl/gl hairs, reveals that yellow pigment is indeed present but that it is distributed mostly in clumps somewhat like the distribution found in dilute and leaden animals. Evidently for some reason grey-lethal melanocytes are unable to release yellow granules in the same manner as black granules. Moreover, inasmuch as this clumping is accompanied by a considerable number of sparsely pigmented or empty hair septules, it is likely, although not proven, that grey-lethal also reduces the number of phaeomelanin granules.
The basis for the effect which grey-lethal has on the deposition and perhaps the synthesis of phaeomelanin is not known. Grüneberg ( 1966c) cites that the hairs themselves are structurally abnormal but, if so, it is difficult to envisage how this would selectively influence phaeomelanin synthesis. 1 The observation that grey-lethal melanocytes in all pigmented tissues except the hair bulbs produce black granules only led Markert and Silvers ( 1956) to conclude that this mutation probably acted "within the epidermal cells of the hair bulb in the presence of Ay, Aw, A and at genes to weaken and render abnormal the stimulus for yellow melanin production." Nevertheless, it is just as likely that gl acts within the melanocyte but produces its effect only after phaeomelanin synthesis is "turned on" by the appropriate a-allele. 2
Also to be resolved is whether the abnormal deposition of phaeomelanin in the form of clumps into the hair of grey-lethal mice reflects a change in the morphology of the follicular melanocytes? Thus it would be of interest to know if during phaeomelanin synthesis the hair bulb melanocytes of A/—;gl/gl animals switch from a nucleofugal to a nucleopetal morphology and whether Ay/—;gl/gl melanocytes persist in the nucleopetal form? This information is particularly important for elucidating the relationship between melanin deposition and melanocyte morphology, including the stability of these cells in the hair follicle (see Chapter 4, Section I, D).
Finally, the fact that grey-lethal [and grizzled ( Section II)] has no apparent influence on eumelanin synthesis is important because it provides further evidence that eumelanin and phaeomelanin are produced via alternative pathways.
As perplexing as grey-lethal's effect on pigmentation is, it is even more difficult to envisage how this influence ties in with the other manifestations of the mutation. Grey-lethals display profound anomalies in their skeleton and teeth ( Doykos et al., 1967; H. Murphy, 1969), abnormalities which stem from their inability to resorb bone. The condition can be identified at birth, even from as early as the eighteenth day of gestation because the apex of the grey-lethal's lower incisor lies anterior to the molar region in the mandible ( Hollinshead et al., 1975). It can be identified also at 2 days of age by the external appearance of amputated tibiae; the diaphyses of normal tibiae appear red under the dissecting microscope due to the presence of hemopoietic tissue occupying the central marrow cavity, whereas grey-lethal tibiae appear opaque because relatively more unresorbed bone occupies the center of the diaphysis ( Hollinshead and Schneider, 1973).
Grey-lethals weigh slightly less than normals at birth but grow steadily although at a somewhat reduced rate during the first 2 weeks. Thereafter, until weaned, their weight either is stationary or increases irregularly. When weaned their weight declines rapidly, especially if they are not allowed to continue to suckle. Under normal conditions grey-lethals die between 21 and 30 days of age ( Grüneberg, 1952). Although one might expect that the main cause of death is starvation as a consequence of noneruption of the teeth, this is not the case since hand-feeding affected animals with a liquid diet prolongs their survival only slightly ( Grüneberg, 1952). Grüneberg suggests that a neuralgia of the trigeminus due to the excess formation of bone matrix makes them reluctant to move their jaws.
As might be expected from a failure of secondary bone absorption, grey-lethals are characterized by widespread anomalies of the skeleton and teeth. A general osteosclerosis prevails in the growing and developing bones, and because osteoclastic activity is deficient, a disfigurement of the osseous architecture results ( H. Murphy, 1969). Hirsch ( 1962) reported a mean osteoclast count of only 11 (SD +/- 10) cells/mm2 in untreated sections of grey-lethal metaphyseal bone, compared with a mean of 74 (SD +/- 19) cells/mm2 in corresponding sections from untreated normal bone. The failure of the teeth to erupt is caused by a lack of resorption in the dental crypts ( H. Murphy, 1969).
To determine the basis of this failure of secondary bone resorption Barnicot ( 1941) performed a number of transplantation experiments. He found that if he transplanted grey-lethal bone to normal hosts it frequently attained a structure approximating that of normal bone whereas this was not the case if the transplant was made to another grey-lethal animal. On the other hand, normal bones transplanted into grey-lethals sometimes, but not always, became structurally similar to grey-lethal bones. Barnicot ( 1945) also observed that grey-lethal animals were very resistant to injections of parathyroid hormone but that massive doses of this hormone, doses which were lethal to normal mice, could induce bone absorption (see also Walker, 1966; Schneider et al., 1972). He also reported that when grey-lethal parathyroid gland and a section of grey-lethal parietal bone were transplanted intracerebrally into normal hosts, the bone adjacent to the gland displayed signs of resorption ( Barnicot, 1948; see also Hirsch, 1962).
Barnicot ( 1945), Hirsch ( 1962), and Grüneberg ( 1963) suggested that these results were consistent with the possibility that grey-lethals produced normal amounts of parathyroid hormone but somehow inactivated or destroyed it at an increased rate. More recently, however, both thyroid and parathyroid endocrinopathies have been shown to be involved (H. Murphy, 1968, 1969, 1972, 1973; Marks and Walker, 1969), and many features of the condition can be explained by an increased secretion of the thyroid hormone, calcitonin, eliciting a compensatory increase in parathyroid hormone ( H. Murphy, 1973). Nevertheless, it is not clear whether even these endocrinological changes are the primary cause of the osteopetrosis. Probably the best hypothesis is one proposed by Marks and his associates ( Marks and Lane, 1976; Marks and Walker, 1976). They suggest that the primary lesion is in the osteoclast, i.e., that a reduction in osteoclast function is responsible for the hyperparathyroidism (and the increase in bone formation), and that the parafollicular cell hyperplasia (and the increased secretion of calcitonin) is a compensatory response to elevated levels of parathormone (see also Raisz et al., 1977).
Most exciting have been the studies of Walker ( 1975a, 1975b, see also 1972). He found that if irradiated grey-lethal mice are given an intravenous inoculation of cells prepared from the spleen or bone marrow of normal littermates, their capacity to resorb bone and calcified cartilage is restored. Conversely, osteopetrosis is induced when lethally irradiated, normal mice are given cell infusions prepared from the spleens of grey-lethal littermates. These results indicate either that cells from normal donors give rise to competent osteoclasts in grey-lethal recipients, or that they are the source of some humoral factor which is essential for normal osteoclast function. 3
Although some of the problems of the grey-lethal mouse appear to stem, at least secondarily, from the malfunctioning of the thyroid and/or parathyroid, the possibility should not be overlooked that the thymus too is involved. This possibility receives support from two observations. First from Grüneberg's ( 1952) observation that the grey-lethal's thymus undergoes a rapid and complete degeneration of the cortex during the third week of life; 4 and second from the fact that the thymus may be involved in the pathogenesis of a genetically determined osteopetrotic condition in rats (which does not affect pigmentation) ( Milhaud et al., 1977). 5 Indeed, "op" rats not only suffer from an early atrophy of the thymus gland, but their condition too can be cured with a single injection of normal bone marrow cells ( Milhaud et al., 1977; see also Marks, 1978a, 1978b).
While it is difficult enough to relate these disturbances in bone formation to an affect on phaeomelanin, they also must somehow be related to white spotting. This follows from the fact that microphthalmia ( mi) homozygotes, which are "one big spot" (see Chapter 12, Section I, A, 2), likewise suffer from an osteopetrotic condition which although not as severe as grey-lethal's apparently has a similar etiology (see Chapter 12, note 5).
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