JAX Notes January 02, 1995

Waved-2 (Egfrwa2) mutant mice

History

Shortly after Crew's description of the waved-1 (wa1) mutation in 1933, Clyde Keeler identified a similar mutation in his "abnormal corpus callosum" stock (Keeler, 1935). This stock was unrelated to his "Berlin blaze" stock that yielded the earlier mouse with wavy hair. The original waved-2 male mouse was outcrossed to four unrelated females. All 22 offspring were normal. Subsequent matings verified the recessive nature of this mutation (Keeler, 1935). Waved-2 (labeled "Keeler wavy") was imported to The Jackson Laboratory from Reed in 1935. It is currently maintained on the B6EiC3H hybrid stock (C57BL/6JEi x C3H/HeSnJ; Sweet, 1994).

Gross lesions

Homozygous (wa2/wa2) mice can be identified at birth or shortly thereafter because they are smaller and have shorter vibrissae than littermate controls (wa2/+ or +/+). Vibrissae appear to be bent by 2 days of age and have a distinct curl by 4-5 days of age. Wavy texture of the pelage appears as it grows in and increases until 6 weeks of age. Between 7 and 8 weeks of age the waviness decreases but does not entirely disappear. Vibrissae and guard hairs remain curled throughout life. Hair length is shorter than normal and hair angle is irregular (Keeler, 1935).

Waved-2 homozygotes with open eyelids at birth have not been observed in either stock maintained at The Jackson Laboratory (Sweet, 1994), although eyelids are open in wa1 or wa2 mutations maintained on other genetic backgrounds (Butler and Robertson, 1953; Taylor and Ivey, 1987).

Microscopic lesions

The degree of changes in hair morphology varies with genetic background. Details of the original description of Reed (1938) have been disputed by McLaren (1971), who conceded that variations in genetic background probably explained the differences. We have examined plucked hairs from mutant mice maintained at The Jackson Laboratory on the B6EiC3H hybrid background. By light or scanning electron microscopy pelage hairs from normal littermate control mice were straight or sharply curved, depending upon their hair type (Sundberg and Hogan, 1994). The diameter of hair shafts gradually decreased toward the distal end regardless of hair type. Guard hairs were round with regular cuticular scales at the proximal end, near the skin. The midshaft of guard hairs had a longitudinal groove with bilaterally symmetrical walls. In contrast, plucked hairs from wa2/wa2 mice had a prominent serpentine pattern.

By scanning electron microscopy the serpentine pattern was evident in all hair types. The distal end of each shaft tapered (decreased in diameter) more rapidly than controls. The proximal ends of guard hairs were flattened and thinned at the site of bends. The midshaft of the guard hairs had a longitudinal groove, but the walls were asymmetrical and the diameter of the shaft was reduced. The cuticular pattern was normal. No fissures or other types of damage were observed. The cause of the bending of the hair shafts in wa2/wa2 mice has been attributed to increased numbers of constrictions in the hairs (Reed 1938) or incomplete or irregular septa between air spaces with variations in width, suggesting a keratinization defect (McLaren, 1971).

Immunological and biochemical abnormalities

Transplantation studies using skin grafts between pigmented and unpigmented normal and wa2/wa2 mice revealed that wa2/wa2 grafts were both autonomous and possessed the ability to alter genetically nonwaved cells to produce waved hairs (Reed 1938). Reed speculated that this was due to production of a growth-inhibiting substance that increased the number of constrictions of each hair, causing a waved hair to be produced.

Chimeras were generated from fusion of embryos using nine different recessive homozygous mutations, including wa2. Hairs from a mixed patch revealed chimerism within as well as between hairs for both pigmentation and waving. Pigmented and non-pigmented areas were evident along the length of the hair shaft. The degree of waviness in chimeric hairs was less than wa2/wa2 controls (McLaren and Bowman, 1969).

Waved-1 is phenotypically similar to waved-2, but maps to mouse chromosome 6 rather than 11. Waved-1 has been shown to affect the transforming growth factor alpha (Tgfa) gene (Mann et al., 1993; Luetteke et al., 1993). It has been proposed that deficiency of either TGFa (as in wa1 and the two null mutations of Tgfa) or its receptor (EGFR) would give rise to similar hair and eye phenotypic abnormalities (Mann et al., 1993; Luetteke et al., 1993). Waved-2 consists of a point mutation in the EGF receptor tyrosine kinase (Luetteke et al., 1994).

Ocular lesions occur in many inbred strains of laboratory mice. Ocular lesions observed in waved-1 and waved-2 mutations may be related to the mutation, however, more extensive work needs to be done to ensure that these are not secondary effects from exposure due to open eyelids or background genetic effects that are common in strains derived from C57BL/6 or C57BL/10 mice.

Analogous human disease

No analogous human disease has been compared to the waved-2 mouse mutant.

Analogous animal disease

A rat mutation known as curly coat is dominant and has a wavy hair coat, similar to waved-1 that becomes progressively worse with age (Crew, 1933). Two or more Rex mutations in rats also have wavy hair coats (Keeler, 1935).

Domestic rabbits are known to have at least three genetically distinct, phenotypically indistinguishable mutations known as rex that have waved hair (Keeler, 1935).

Several other mouse mutations have curly pelage hairs and/or vibrissae. These include curly whiskers (cw, Chr 9), frizzy (fr, Chr 7), fuzzy (fz, Chr 1) 3 alleles at the rex gene (Re; opossum, Reop; and wavy coat, Rewc; Chr 11), waved-2 (wa2, Chr 11), wellhaarig (we, Chr 2), and others. These are reviewed in detail elsewhere (Green, 1989; Sundberg, 1994; Sundberg et al. 1994).

Two null mutations of the Tgfa gene were created independently. Both are virtually identical to waved-1 and have been shown to be alleles in breeding studies (Mann et al., 1993; Luetteke et al., 1993).

Common uses of the waved-2 mutation

Waved-2 has been used to investigate the interaction between genes that cause abnormalities of the hair (Snell, 1939; Carter, 1951; McLaren and Bowman, 1969).

This mutation is currently being used to investigate the functions of epidermal growth factor receptor (EGFR) on skin biology and pathology. The biology of EGF and its receptor can now be investigated when panels of mouse mutations with known or presumed abnormalities are used. Other mutations with abnormalities of EGF and/or EGFR include crinkled (cr), downless (dl), sleek (Dlslk) and tabby (Ta). These are reviewed in detail elsewhere (Sundberg, 1994; Sundberg, et al. 1994).

Availability

The waved-2 mutation is maintained by The Jackson Laboratory Mouse Mutant Resource in the B6EiC3H a/A wa2 vt hybrid stock (B6EiC3Sn a/A-Egfrwa2 Wnt3avt/J - 000553). This hybrid and the STOCK a/a wa2/+ (STOCK a/a Egfrwa2/J - 000317) strain are preserved in The Jackson Laboratory Frozen Embryo Repository.

References

Butler L, Robertson, DA. A new eye abnormality in the house mouse. J Hered 44:13-16, 1953.

Carter TC. Wavy-coated mice: phenotypic interactions and linkage tests between Rex and (a) waved-1, (b) waved-2. J Genet 50:268-276, 1951.

Crew FAE. Waved: an autosomal recessive coat form character in the mouse. J. Genet 27:95-96, 1933.

Green MC. Catalog of mutant genes and polymorphic loci. In: Lyon, M.F. and Searle, A.G., ed., Genetic Variants and Strains of the Laboratory Mouse 2nd ed., Oxford Univ. Press, Oxford, pp. 12-403, 1989.

Keeler CE. A second rexoid coat character in the house mouse. J Hered 26: 189-191, 1935.

Luetteke NC, Qiu TH, Peiffer, RL, Oliver P, Smithies O, Lee DC. TGFa deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell 73:263-278, 1993.

Luetteke NC, Phillips HK, Qiu TH, Copeland NG, Earp HS, Jenkins NA, Lee DC. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Devel 8:399-413, 1994.

Maltais LJ, Hillyard AL, Doolittle DP, Davisson MT, Guidi JN, Roderick TH. GBASE, the genomic database of the mouse. Maintained at The Jackson Laboratory, 1994.

Mann GB, Fowler KJ, Gabriel A, Nice EC, Williams RL, Dunn AR. Mice with a null mutation of the TGFa gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell 73:249-261, 1993.

McLaren A. The microscopic appearance of waved-2 mouse hairs. Genet Res 17:257-260, 1971.

McLaren A, Bowman P. Mouse chimeras derived from fusion of embryos differing by nine genetic factors. Nature 224:238-240, 1969.

Reed SC. Determination of hair structure. I. The production of waved hair from genetically non-waved cells. J Exp Zool 79:347-354, 1938.

Smith RS, Roderick TH, Sundberg, JP. Microphthalmia and associated abnormalities in inbred black mice. Lab Anim Sci in press.

Snell GD, Law LW. A linkage between shaker-2 and wavy-2 in the house mouse. J Hered 30:447, 1939.

Sundberg JP. Mouse Mutations with Skin and Hair Abnormalities; Animal Models and Biomedical Tools. CRC Press, Boca Raton, 1994.

Sundberg JP, Smith RS, Hogan Me. The waved-1 (wa-1) mutation, Chromosome 6. JAX Notes 459:2-5, 1994.

Sweet HO. Origin of wa-2 maintained at The Jackson Laboratory. JAX Notes 456:5, 1994.

Taylor BA, Ivey JM. New allele of waved-1 with open eyes at birth. Mouse News Lett. 77:129, 1987.