Mt. Lewis et al., Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1, DEVELOPMENT, 126(22), 1999, pp. 5181-5193
In vertebrates, the hedgehog family of cell signaling proteins and associat
ed downstream network components play an essential role in mediating tissue
interactions during development and organogenesis, Loss-of-function or mis
expression mutation of hedgehog network components can cause birth defects,
skin cancer and other tumors. The mammary gland is a specialized skin deri
vative requiring epithelial-epithelial and epithelial-stromal tissue intera
ctions similar to those required for development of other organs, where the
se interactions are often controled by hedgehog signaling, We have investig
ated the role of the Patched-1 (Ptc1) hedgehog receptor gene in mammary dev
elopment and neoplasia, Haploinsufficiency at the Ptc1 locus results in sev
ere histological defects in ductal structure, and minor morphological chang
es in terminal end buds in heterozygous postpubescent virgin animals, Defec
ts are mainly ductal hyperplasias and dysplasias characterized by multilaye
red ductal walls and dissociated cells impacting ductal lumens, This phenot
ype is 100% penetrant, Remarkably, defects are reverted during late pregnan
cy and lactation but return upon involution and gland remodeling. Whole mam
mary gland transplants into athymic mice demonstrates that the observed dys
plasias reflect an intrisic developmental defect within the gland. However,
Ptc1-induced epithelial dysplasias are not stable upon transplantation int
o a wild-type epithelium-free fat pad, suggesting stromal (or epithelial an
d stromal) function of Ptc1, Mammary expression of Ptc1 mRNA is both epithe
lial and stromal and is developmentally regulated. Phenotypic reversion cor
relates with developmentally regulated and enhanced expression of Indian he
dgehog (Ihh) during pregnancy and lactation. Data demonstrate a critical ma
mmary role for at least one component of the hedgehog signaling network and
suggest that Ihh is the primary hedgehog gene active in the gland.