Slits and netrins are well-known neural guidance cues. However, on , Strickland et al. report that these proteins also act as adhesive cues during mammary gland development, thus providing new insights into ductal morphogenesis. The bilayered branched epithelial tubes of the mammary gland contain an outer cap/myoepithelial cell layer and an inner luminal epithelial layer. The researchers show that both layers express SLIT2 during duct elongation but that only the cap/myoepithelial cells express ROBO1, the SLIT2 receptor. Mice lacking both Slit2 and Robo1 have disorganized ductal end buds, which resemble those of mice lacking netrin 1(Ntn1-/- mice). Slit2-/-;Ntn1-/- glands have an even more extreme phenotype that is characterized by the separation of the two ductal cell layers. The researchers confirm this is an adhesive defect by showing that Slit2-/-;Ntn1-/- cells fail to form bilayered organoids in vitro. They conclude that SLIT2 and NTN1 act in parallel as adhesive cues to preserve the bilayer structure of the mammary gland during morphogenetic modelling.
