Chapter 11

Steel, Flexed-Tail, Splotch, and Varitint-Waddler

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II. Flexed-Tailed ( f)

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

Flexed-tailed (f), a recessive spotting determinant on the thirteenth chromosome, appeared in a stock maintained by H. Hunt ( 1932; H. Hunt et al., 1933). It receives its name from the fact that f/f mice have flexed tails, as well as occasional fusions of other vertebrae ( H. Hunt et al., 1933; Kamenoff, 1935). This mutation also produces a transitory siderocytic anemia. Indeed, it is this condition which has received the most attention. While it is beyond the scope of this review to present a detailed analysis of the nonpigmentary effects of this mutation (see Grüneberg, 1952; E. Russell and Bernstein, 1966; E. Russell et al., 1968, 20 they nevertheless deserve some consideration for the bearing they may have on the etiology of the white spotting. This is especially the case since we are again dealing with a spotting gene which has a major influence on erythropoiesis. Thus before considering flexed-tailed's influence on pigmentation, its morphological and hematological consequences are briefly described.

A. Influence on Tail

The most obvious effect of f when homozygous is the flexures of the tail it produces. These are highly variable ( H. Hunt et al., 1933). As a rule there are one or more permanent angles in the tail, though occasionally there may be as many as five. These may be acute, obtuse, or right angles, occurring most frequently in the proximal half of the tail, though sometimes one occurs near the tip. In addition to these flexures the tail may be significantly shortened. The tail is usually very stiff where the flexures occur and even when there is no visible flexure palpation mat reveal rigid areas. These stiff regions in tails which appear straight may be so small, and approach the normal so closely in flexibility, that it is often difficult to classify some f/f animals solely on the basis of their tails ( H. Hunt et al., 1933). In fact, in some populations the tails of as many as 45 - 50% of f/f mice appear normal ( Clark, 1934).

The development of the tail anomalies of f/f mice has been investigated by Kamenoff ( 1935) who found that there was an ankylosis of vertebrae which could be accounted for by an anomaly of the intervertebral disks. This disk consists of the nucleus pulposes, which stems from the notochord and is surrounded by a hyaline sheath, and the annulus fibrosus, which consists of felted connective tissue fibers which form a ring round the nucleus pulposes. In normal embryos the early cartilage, which later forms the annulus fibrosus, differentiates into fibers on the fourteenth to fifteenth day of gestation. However, in flexed embryos, this differentiation of fibers is disturbed, and in places does not take place at all. As a consequence as many as 10 or more successive tail vertebrae may be joined by cartilage bridges which subsequently ossify. If this happens on one side of the intervertebral disc, flexing occurs, and if it occurs on both sides, a stiff fusion without flexure results.

B. Anemic Condition

In addition to f's effect on the tail, Hunt noted early in his experiments that flexed-tailed young were considerably lighter in color than their normal tailed littermates. He suspected that this was because they were anemic and this suspicion was confirmed when their blood was compared with their normal tailed siblings ( Mixter and H. Hunt, 1933). 21 The anemia is a microcytic one, characterized by a high frequency of siderocytes 22 (Grüneberg, 1942b, 1942c), which seems almost to disappear after the first week of postnatal life. 23

Because initial studies suggested that this anemia could be detected only after erythropoiesis was initiated in the liver on the twelfth day of gestation, and because it is most severe during that period of gestation (thirteenth to sixteenth day) when the liver is the only erythropoietic organ (after the sixteenth day the burden of erythropoiesis is gradually assumed by the bone marrow), the anemia originally was believed to be due to a disturbance of the hematopoietic function of this organ ( Kamenoff, 1942; Grüneberg, 1942b). A more recent study ( E. Russell et al., 1968), however, has revealed that the anemia is sufficiently severe on the twelfth day of gestation (when only primitive nucleated erythrocytes of yolk sac origin are present) to indicate that it is not transitory and that all generations of erythrocytes are affected. This conclusion is further supported by the observation that adult flexed-tailed mice also display abnormalities of hemopoiesis when placed under conditions of physiological stress ( Margolis and E. Russell, 1965; Thompson et al., 1966; Fowler et al., 1967; Coleman et al., 1969; see also Gregory et al., 1975). Thus, during recovery from phenylhydrazine-induced anemia there is a delay in reticulocyte production in f/f animals ( Coleman et al., 1969), and hemopoietic stem cells from these mice do not proliferate normally in lethally irradiated hosts ( Thompson et al., 1966).

Although the specific cause of the hemopoietic defect produced by f when homozygous is not known, a recent investigation by Chui and his associates ( 1977) indicates that there is a relative excess of free heme in f/f cells. For this reason they suggest "that one effect of the mutant f gene product is to interfere with the normal expression of globin genes during fetal erythropoiesis, leading to decreased production of globin chains, hypochromic microcytic anemia, and a relative excess of intracellular free heme pool due to decreased utilization." [For other hematological investigations of flexed-tailed see A.E. Bateman and Cole ( 1972) and A.E. Bateman et al. ( 1972)].

C. White Spotting

The white spotting associated with the f/f genotype, like the tail flexures, is variable in its expression. Although many flexed-tailed mice have a white spot about 2 cm in diameter on their abdomen, in segregating populations the size of the spot varies from no spot at all (normal overlap) to an unpigmented area covering most of the ventral surface. In rare cases the spot is even larger, extending up the sides to form a partial belt. Mice which display white spotting have white toes and may or may not have a spot on the tip of the tail ( Clark, 1934).

As in the case of the tail abnormality, the incidence of white spotting in f/f mice depends upon the genetic background. Whereas in some genetically uniform stocks all f/f mice show a moderate degree of white spotting ( E. Russell and McFarland, 1966), in some heterogeneous populations from 40 to 45% normal overlaps have been reported ( Clark, 1934).

D. Combined Influence of Flexed-Tailed and Dominant Spotting

Inasmuch as f and W combine effects on quality and distribution of hair pigmentation with pathological effects on erythropoiesis, it was of interest to determine how these genes would affect these traits when they occurred together. This was pertinent not only insofar as providing information on the etiology of the anemias, but of the white spotting as well. It follows that if the white spotting produced by these genes is in some way a secondary effect of the anemia, then the combined effect of W and f should have a similar influence on both conditions.

To investigate this E. Russell and her associates (E. Russell and McFarland, 1965, 1966; E. Russell et al., 1968) established congenic stocks differing at the W and f loci so that all possible combinations of W- and f-locus genotypes could be compared on the same uniform genetic background. They found, insofar as the white spotting was concerned, that W/+ and f/f acted synergistically. Whereas the ventrums of W/+ and +/+;f/f displayed similar amounts of white spotting, and there was almost no white on their backs, W/+;f/f animals displayed much more than the sum of the amounts of white produced by W/+ and f/f alone ( E. Russell and McFarland, 1966). This hyperadditive effect of w/+;f/f was particularly striking on the dorsum where the amount of spotting was increased from 1% or less to more than 20% (see Table 11-3 and Figure 11-1).

In contrast to the hyperadditive influence of W/+;f/f on spotting the effect of this genotype on the blood was exactly what one would anticipate from the combination of effects of W/+ versus +/+ and of f/f versus f/+ genic substitutions. Thus, there was no evidence of an association between the amount of white spotting (much higher in W/+;f/f than in +/+;f/f mice) and the degree of anemia (similar in W/+;f/f and +/+;f/f mice). The evidence is therefore consistent with the notion that in the case of W, and probably in the case of f/f, white spotting results from an independent primary gene effect on pigment-forming cells ( E. Russell and McFarland, 1966).

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