Think globally, act locally: the making of a mouse mammary gland.

On a phylogenetic scale of organ development the mammary gland is a recent acquisition. It was introduced 200 million years ago with the appearance of mammals to provide nourishment to the newborn in the form of milk. The mammary gland is characterized by a unique dependence on hormonal signals for terminal differentiation, which is attained only after pregnancy. At the time of birth, the anlage consists of a few rudimentary ducts in the vicinity of the nipple. Pronounced ductal outgrowth and branching commences at puberty, and in pregnancy an expanded lobulo-alveolar compartment develops. Functional differentiation of the secretory epithelium coincides with parturition and large amounts of milk are produced and secreted during lactation. After weaning of the young, the entire alveolar epithelial compartment is remodeled to resemble a virgin-like state. With each pregnancy, a new round of lobulo-alveolar development occurs. During the past 100 years, intensive efforts have been made to understand the endocrine control of mammopoiesis and lactogenesis. Classical research on endocrine ablated animals firmly established that ovarian steroids and pituitary peptide hormones are mandatory and sufficient for breast development and lactation. In 1900, Halban first established that mammary growth is controlled by the ovary (Halban 1900). He demonstrated that ovariectomy caused mammary regression, and that transplanted ovaries prevented the castration atrophy of mammary glands. Twenty-eight years later, Stricker and Grueter induced mammary development and milk secretion artificially in castrated virgin rabbits by injection of pituitary extract (Stricker and Grueter 1928). In 1933, Riddle, Bates, and Dykshorn purified the respective pituitary hormone (Riddle et al. 1933) and named it prolactin(PRL). In the last several years, the ability to delete genes from the mouse genome has allowed us to identify genetic components of mammary gland development. Molecular insight into the underlying genetic framework and signaling networks of the developing tissue has been gained through experimental manipulations of tissues from wild-type and knockout mice. Two distinct, yet braided, developmental concepts have unfolded. First, discrete signaling networks activated by systemic endocrine hormones induce mammopoiesis. Secondly, some of these signals are relayed through reciprocal interactions between the epithelium and the stroma. Table 1 contains those genes whose elimination from the mouse genome results in impaired mammary gland development. Among these genes are some of the ‘‘usual suspects’’ but also some previously unidentified players. Each mutation affects specific and distinct aspects of mammary development. These knockout mice not only confirmed the involvement of hormonal signaling but also provided tools to identify the tissue compartment that receives and executes these signals.