Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1

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.