Mammary gland patterning in the AXB/BXA recombinant inbred strains of mouse

In mice, ®ve pairs of mammary glands are distributed in a cranial to caudal sequence on the ventral body wall starting slightly anterior to the forelimbs and extending to the hindlimbs. Little is known about the inductive signals that initiate mammary gland formation and patterning. Mammary glands develop during embryogenesis as a result of reciprocal epithelial±mesenchymal interactions (Cunha et al., 1992; Cunha, 1994; Cunha and Hom, 1996). The mammary glands are arranged as bilaterally symmetric series of organs with no obvious relationship to the basic vertebrate segmentation that occurs earlier during embryogenesis (Bateson, 1894). How the number and spacing of mammary glands is achieved is unknown. De®ciencies and supernumerary mammary glands in inbred strains of mice have been reported and were postulated to have a genetic basis (Gardner and Strong, 1935; Little and McDonald, 1965). We have shown that one major autosomal recessive trait is responsible for the scaramanga (ska) mutation, which is involved in the determination of pattern formation of the mammary gland in mouse (Howard and Gusterson, 2000). The ska mutation was characterized in an inbred strain of mice (A/J) that displays supernumerary mammary glands and nipples, misplaced nipples, and mammary gland de®ciencies. We report here the results of genetic studies in this system using recombinant inbred (RI) strains produced between the A/J and C57BL/6 (B6) strains. 16 AXB RI and 14 BXA RI strains were obtained from The Jackson Laboratory strains and the mammary gland patterning phenotypes were determined (The Jackson Laboratory, Bar Harbor, ME, USA) (Marshall et al., 1992). We have characterized the phenotypic variation of the ska mammary gland pattern mutant phenotype within the A/J, B6, and 30 AXB/BXA RI strains of mice (Table 1). ska mammary gland pattern abnormalities include absent #3 glands, misplaced #3 glands, and supernumerary nipples connected to a functional, milk-producing ductal system that is distinct from that of the normally occurring gland (Fig. 1). All 75 B6 mice displayed a normal mammary gland pattern, consisting of 5 pairs of glands spaced linearly and bilaterally symmetrically along the body's ventral surface. 95.2 percent of A/J mice (40/42) displayed abnormal mammary gland patterns. Penetrance levels of the total ska mammary gland pattern mutant phenotypes were similar to those of the parental strains, except in the BXA-17 strain where it displayed an intermediate value of 45.5 percent. This suggests the presence of modi®er loci that affect the probability of whether abnormal mammary gland patterns will form or not. The distribution of mammary gland pattern phenotypes varies greatly throughout the AXB/BXA RI set which strongly suggests that modi®er genes also in ̄uence the type of phenotype that is likely to arise in that genetic background. It should be possible to map such factors to better understand the nature of the process of mammary gland development. The variability of the ska mammary gland mutant phenotypes within genetically identical backgrounds suggest that genes affecting mammary gland development may be especially prone to modi®cation by other genes and environmental factors. A human syndrome with similar variable mammary phenotype exists. Mutations in the human TBX3 gene (a member of the T-box gene family) cause ulnarmammary syndrome, a pleiotropic disorder (Bamshad et al., 1997). Women and men with ulnar-mammary syndrome may have hypoplastic, absent or extra mammary structures as well as abnormal limb, apocrine gland, tooth, and genital development (Bamshad et al., 1997). Another human disorder with pleiotropic genetic features is limb mammary Mechanisms of Development 91 (2000) 305±309