Prolactin controls mammary gland development via direct and indirect mechanisms

The inactivation of the prolactin receptor gene by homologous recombination has made it possible to investigate the role of prolactin signaling in mam mary gland development without resort to ablative surgery of the endocrine glands. In knockout mice lacking the prolactin receptor, mammary developmen t is normal up to puberty. Subsequently, the ducts branch less frequently t han those of wild-type animals. While terminal end buds differentiate to al veolar buds in wild-type females by the end of puberty, in knockout females terminal end bud-like structures persist at the ductal ends. To distinguis h between the developmental defects that are intrinsic to the epithelium an d those that result from systemic endocrine alterations in prolactin recept or knockout mice, mammary epithelium from prolactin receptor knockouts was transplanted into mammary fat pads of wild-type mice. In virgin mice, the k nockout epithelial transplants developed normally at puberty, indicating an indirect effect of prolactin on ductal development. Prolactin receptor kno ckout females are infertile due to multiple reproductive defects, but epith elial transplants allowed us to assess the extent to which the absence of p rolactin receptor is limiting, under systemic conditions that allow full ma mmary gland development. During pregnancy, the prolactin receptor knockout transplants showed normal side branching and the formation of alveolar buds , but no lobuloalveolar development. Thus, prolactin affects mammary morpho genesis in two different ways: it controls ductal side branching and termin al end bud regression in virgin animals via indirect mechanisms, but acts d irectly on the mammary epithelium to produce lobuloalveolar development dur ing pregnancy. (C) 1999 Academic Press.