Our results demonstrate that Dkk-1 is an LRP6 ligand and inhibits Wnt signaling by blocking Wnt-induced Fz-LRP6 complex formation. Our findings thus reveal a novel mechanism for Wnt signal modulation. LRP6 is a Wnt coreceptor that appears to specify Wnt/Fz signaling to the beta-catenin pathway, and Dkk-1, distinct from Wnt binding antagonists, may be a specific inhibitor for Wnt/beta-catenin signaling. Our findings suggest that Wnt-Fz-LRP6 complex formation, but not Wnt-Fz interaction, triggers Wnt/beta-catenin signaling.

The formation of precise connections between retina and LGN involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the MHC Class I (MHCI) molecule H2-Db is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-Kb and H2-Db (KbDb−/−) despite intact retinal activity and basal synaptic transmission, the developmentally-regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-Db in KbDb−/− mice rescues both synapse elimination and eye specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, LTP is intact but LTD is impaired in KbDb−/− mice. This change is due to an increase in Ca2+ permeable AMPA receptors. Restoring H2-Db to KbDb−/− neurons renders AMPA receptors Ca2+ impermeable and rescues LTD. These observations reveal an MHCI mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-Db in functional and structural synapse pruning in CNS neurons.

Dickkopfs (Dkks) are secreted developmental regulators composed of two cysteine-rich domains. We report that the effects of Dkks depend on molecular context. Although Wnt8 signaling is inhibited by both Dkk1 and Dkk2 in Xenopus embryos, the same pathway is activated upon interaction of Dkk2 with the Wnt coreceptor LRP6. Analysis of individual Dkk domains and chimeric Dkks shows that the carboxy-terminal domains of both Dkks associate with LRP6 and are necessary and sufficient for Wnt8 inhibition, whereas the aminoterminal domain of Dkk1 plays an inhibitory role in Dkk-LRP interactions. Our study illustrates how an inhibitor of a pathway may be converted into an activator and is the first study to suggest a molecular mechanism for how a ligand other than Wnt can positively regulate ␤-catenin signaling.