A Ror recruit to mammary gland development

All signaling pathways have their complexities , but Wnt signaling may be more complex than most. There are 19 different Wnt ligands in mammals that bind to multiple types of receptors, some of which activate a canonical pathway that stabilizes the tran-scriptional coactivator ␤-catenin, and some of which signal via noncanonical, ␤-catenin– independent pathways. Roarty et al. begin to unpick the cross talk between Wnt ligands and receptors during mammary gland development and reveal a crucial role for the noncanonical receptor Ror2 (1). Mammary gland development mainly occurs postnatally. The ducts formed by the bilayered mammary epithelium extend and branch at puberty and then, during pregnancy , differentiate into milk-producing alveoli. Multiple Wnt ligands are expressed in the mammary gland (2, 3), and ␤-catenin's transcriptional activity is required for these developmental processes and for mammary stem cell self renewal (4, 5). " But no one really knew what the role of noncanonical receptors and ligands were, " explains Jeffrey Rosen from Baylor College of Medicine in Houston, Texas. Rosen and colleagues, led by postdoc Kevin Roarty, initially found that the nonca-nonical receptors Ror1 and Ror2, and their ligands Wnt5a and Wnt5b, were expressed in mouse mammary epithelium (1). Ror1 and Ror2 were expressed in both the basal and luminal cell layers but their distribution was distinct from that of canonical Wnt sig-naling. A reporter of ␤-catenin tran-scriptional activity showed that canonical Wnt signaling was primarily active in the Cap cells in the terminal end buds of mam-mary epithelial ducts, which are thought to be enriched in mammary stem cells. This activity declined in the more differentiated basal myoepithelial cells further along the ducts, which, in contrast, expressed increased levels of Ror2. " [Canoni-cal and noncanonical signaling] seemed to be inversely correlated, " says Roarty. " This provided evidence for us to pursue some functional studies. " Ror2 and its ligand Wnt5a have been shown to antagonize canonical Wnt sig-naling during embryogenesis (6), and the inverse relationship between Ror2 expression and ␤-catenin activity suggested that the pathways might operate similarly in mammary gland development. Indeed, in primary mammary epithelial cells in vitro, Wnt5a inhibited ␤-catenin activation by the canonical ligand Wnt3. Overexpressing Ror2 enhanced this antagonism, whereas knocking down the receptor blocked Wnt5a's inhibitory effect. To investigate Ror2's function in vivo, Roarty et al. transplanted Ror2-deficient cells into mouse fat pads and followed their development into mam-mary ducts. " There was …