Chapter 9

White Spotting: Piebald, Lethal Spotting, and Belted

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III. Lethal Spotting ( ls)

For the ls allele:
ls Allele (MGI) Gene (MGI) All Alleles (MGI)

This recessive determinant on chromosome 2 ( R.J.S. Phillips, 1966b) is similar to piebald, especially piebald-lethal, It arose in a subline of C57BL in which a mutation to at (which is linked to ls) previously had occurred (R.J.S. Phillips, 1958, 1959).

A. Spotting Patterns and Survival of Homozygotes

While the coats of lethal spotting heterozygotes are fully pigmented, homozygotes show variable degrees of white spotting on the back, and their belly is usually white ( Figure 9-4). Phenotypically these animals therefore resemble s/s mice except that their ears and tail are less pigmented than is usually the case with piebald ( Lane, 1966). Although on some genetic backgrounds ls homozygotes usually die with megacolon at between 2 and 3 weeks of age, and even the few which have lived to breed eventually succumb to this condition ( Lane, 1966), on other backgrounds these homozygotes survive quite well. Thus R.J.S. Phillips informs me that ls is maintained as a homozygous stock at Harwell with only about 6-7% actual deaths before weaning and with no indication that the incidence of megacolon is any higher than in s/s animals.

Histological preparations of the colons of two 12-day-old ls homozygotes from a "lethal" stock, when compared with the colons of two normal ( ls/+ or +/+) siblings of the same age, revealed an identical situation with that in piebald-lethal. The mutants displayed a deficiency of myenteric ganglion cells with the distal section of the colon aganglionic and the most proximal part more or less normal ( Lane, 1966).

B. Influence on the Occurrence of Melanocytes

A comparison of the pigmentation of various tissues of ls/ls and ls/+ mice with those of +/+ animals disclosed a number of differences (see Table 9-2). The harderian gland, leg musculature, ankle skin, and the choroid of ls homozygotes all lacked melanocyte populations, and the number of cells in the membranous labyrinth of these animals was considerably reduced. Thus reduction was not related to the degree of spotting as not only did animals displaying less spotting show the same extent of nonepidermal pigment reduction, but ls/+ mice, which have normally pigmented coats, also exhibited less pigment in their harderian glands, ankle skin, and especially their leg musculature. Four-week-old ls/+ mice were found to possess a total of only 73 +/- 30 melanocytes in the leg musculature as compared to 308 +/- 68 cells in +/+ animals of similar age. Nevertheless, only the coat pigment of ls/ls mice showed the mosaic or pattern effect, i.e., the other regions displayed a dilution and finally a complete loss of pigment ( Mayer and Maltby, 1964).

C. Etiology

In an effort to determine the basis of spotting in ls/ls genotypes, Mayer and Maltby grafted skin from midway between the two limb buds (a region most likely to show spotting in ls/ls individuals) of 12.5- and 13.5-day-old embryos to embryos to the coelom of the chick. However, because in the stock employed ls/ls homozygotes usually die before weaning, these grafts had to originate from embryos derived from ls/+ matings; consequently only one-quarter of them would be expected to be ls/ls. Accordingly only 14 grafts representing 10 of 45 donors were recovered which indicated their genotype to be ls/ls. Nine of these grafts were mosaics possessing both pigmented and pigment-free hairs and the other five contained only unpigmented hairs. Because no pigmentation was associated with this latter group of transplants, i.e., melanocytes were not found in either their dermis or in the coelomic lining of the host surrounding them, and because the mosaic grafts contained pigmented and pigment-free hair located in separate regions such that white hair follicles were always surrounded by a dermis that lacked melanocytes. Mayer and Maltby believe that the white crest areas of ls/ls mice totally lack pigment cells as a result of some neural crest deficiency. Further support for such a defect stems from their megacolon deficiency.

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