Molecular mechanisms guiding embryonic mammary gland development

Abstract

The mammary gland is an epidermal appendage that begins to form during embryogenesis, but whose development is only completed during pregnancy. Each mammary gland begins as a budlike invagination of the surface ectoderm, which then gives rise to a simple duct system by birth. Subsequent development occurs during sexual maturation and during pregnancy and lactation. In this review, we outline the distinct stages of embryonic mammary development and discuss the molecular pathways involved in the regulation of morphogenesis at each stage. We also discuss the potential relevance of embryonic breast development to the pathophysiology of breast cancer and highlight questions for future research.

Figure 1.

Overview of embryonic mammary development.

Figure 2.

Histology of different stages during embryonic mammary development. (A) Early bud stage at embryonic day 12.5, (B) Fully formed mammary bud at E14.5, (C) Male bud at E14.5. Under the influence of testosterone, the mesenchymal cells condense around the stalk of the bud (arrowheads), severing the connection to the epidermis, (D) Mammary Sprout at E18.5, (E) Whole mount of the mammary duct system at postnatal day 2.

Figure 3.

Mammary line specification. Early Wnt signaling (candidate Wnts 3, 6, 10b, 5a, and 11) in a broad band along the flank is required for the formation of the mammary line and all placodes. Fgf10 secreted by cells at the tip of somites and other mesenchymal FGF signals provide vertical signals that integrate with lateral Wnt signals to focally augment Tbx3 expression along the mammary line. Tbx3 is constrained by antagonism from ventral Bmp4. Tbx3 and Nrg3 (N) stimulate Wnt 10b and Lef1 expression. Thus Wnt10b and Lef1 become elevated along the mammary line in a punctate fashion that mirrors the positions of the underlying somites.