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.