Wand Sl Phenotypes

Numerous W mutations, mostly spontaneous in origin, and numerous Sl mutations, both spontaneous and generated by irradiation, have been described in mice (1-4,6). The most severe of these mutations lead to extreme anemia and in utero or perinatal lethality. Mice with milder manifestations may be viable through adulthood and show varying degrees of the classic defects in hematopoiesis, melanogenesis, and gametoge-nesis. The range of W and Sl mutant phenotypes clearly indicates that c-kit and SCF play roles in cell migration, proliferation, differentiation, and function in these various tissue systems during embryonic development and/or in derivative adult tissues.

W and Sl mutant animals can be deficient in the migration of melanoblasts from the neural crest during embryogenesis and in homing of the presumptive melanocytes to the (epi)dermis and hair follicles. Differentiation of melanoblasts to mature melanocytes in the epidermis can be defective. The resulting phenotypes can include lack of pigmentation in various tissues, most notably the skin and coat hairs, leading to white spotting or coat-color dilution (and a resulting silver, roan, or steel appearance) either uniformly or ventrally. In addition, pigmentation in the iris of the eye can be impaired, but the retina is generally pigmented (i.e., black-eyed phenotype).

With respect to gametogenesis and fertility, W and Sl mutant animals can be deficient in the migration of primordial germ cells from the base of the allantois to the genital ridges during embryogenesis. Viable adults can have defects in oogenesis or spermatogenesis (particularly at the spermatogonia stages) and are typically sterile.

Normal embryonic hematopoiesis in the mouse occurs in the yolk sac blood islands during d 7-11 and then in the fetal liver until about d 17. Hematopoietic activity begins in the fetal spleen about d 15 and begins in fetal bone marrow near the end of gestation, continuing throughout life in both tissues. Mature hematopoietic status in the adult animal is reach by about 8-10 wk after birth. In W and Sl mutant animals, erythropoiesis and other aspects of hematopoiesis in the embryonic yolk sac and fetal liver can be impaired. Defects in hematopoiesis after birth are described in detail in Subheading 7.1.

In addition to the phenotypic characterizations, classical transplantation and embryo fusion studies established that, in all affected tissue types, the defects in W mutant animals were intrinsic to the affected cells and the defects in Sl mutant animals affected other cells in the microenvironment upon which the W-expressing cells were dependent (1-4,6).

The elegant genetic and functional studies of the characteristics of W and Sl mutant animals provided a remarkably rich background for further studies after the products of the loci were identified as c-kit and SCF.

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