One possibility is relative ligand specificity, and this may be influenced by the presence of LDLR repeat sequences in the extracellular domains. Although the extracellular domains are highly conserved between the two receptors, the LDLR repeats demonstrate significantly lower sequence homology. In addition, the extraceullar domain of Lrp6 contains 10 putative glycosylation sites, whereas Lrp5 only contains 5, which may also play a role in directing ligand specificity. Another possible mechanism leading to the divergent functions of Lrp5 and 6 may be cell surface presentation and intracellular processing of the receptors. Internalization of Lrp6 has been found to be regulated by clathrin, caveolin,BKM120 ligand interaction and c-secretase-dependent mechanisms, indicating Lrp6 activity can be regulated by different internalization patterns. Although the internalization mechanism of Lrp5 is unknown, it likely differs from that of Lrp6, since the intracellular domains are much less conserved. It is likely that Wnt ligands have specific cognate Frizzled receptors. This specificity has been demonstrated for Wnt5A, which can induce canonical signaling only when Fzd4 and Lrp5 are present. Wnt5A is known to be expressed and bioactive during mouse mammary gland development; a gain of function inhibits ductal outgrowth,BMN673 and loss promotes hyperpro-liferation. Most Fzd mRNAs are expressed in virgin ductal mammary glands, except for Fzd4. If Fzd4 is expressed, it is a very low level, or in a very small subpopulation. The overall output of canonical and other responses depends upon the relative amount of receptors and ligands. Non-canonical and canonical pathways can inhibit each other, and even non-productive interactions can compete with normal signaling activities. It is possible that Lrp5 binds Wnt5A during normal development, but the absence of Lrp5 enhances the inhibitory effects of Wnt5A on ductal outgrowth. Although the embryonic outgrowth of mammary rudiments is Wnt-dependent, the phenotype of early mammary development of Lrp52/2 mice is only marginally affected.